Original Article
Immunochemical Characterization of Circulating Parathyroid Hormone–Related Protein in Patients with Humoral Hypercalcemia of Cancer
N Engl J Med 1990; 322:1106-1112April 19, 1990
- Abstract
- Abstract
Tumors from patients with humoral hypercalcemia of cancer produce a parathyroid Hormone-Related protein (PTHRP). We have developed two region-specific immunoassays capable of measuring PTHRP in plasma: an immunoradiometric assay directed toward PTHRP amino acid sequence 1 to 74 and a radioimmunoassay directed toward PTHRP amino acid sequence 109 to 138.
Sixty normal subjects had low or undetectable plasma PTHRP(1 to 74) concentrations (mean, 1.9 pmol per liter) and undetectable PTHRP(109 to 138) concentrations (<2.0 pmol per liter). Patients with humoral hypercalcemia of cancer (n = 30) had elevated levels of both PTHRP(1 to 74) (mean, 20.9 pmol per liter) and PTHRP(109 to 138) (mean, 23.9 pmol per liter). The plasma concentrations of immunoreactive PTHRP correlated with the levels of urinary cyclic AMP excreted; in some patients, the concentrations decreased after the tumors were resected. Patients with chronic renal failure (n = 15) had plasma PTHRP(1 to 74) concentrations similar to those in the normal subjects, but their plasma PTHRP(109 to 138) concentrations were elevated (mean, 29.6 pmol per liter). The levels of both peptides were normal in patients with hyperparathyroidism and those with hypercalcemia due to various other causes. Breast milk contained high concentrations of PTHRP. An anti-PTHRP(1 to 36) immunoaffinity column failed to extract PTHRP(109 to 138) immunoactivity from plasma, suggesting that the C-terminal region circulates as a separate peptide.
We conclude that plasma PTHRP concentrations are high in the majority of patients with cancer-associated hypercalcemia and that the circulating forms of PTHRP in such patients include both a large N-terminal (1 to 74) peptide and a C-terminal (109 to 138) peptide. Measuring the concentrations of PTHRPs may be useful in the differential diagnosis of hypercalcemia. (N Engl J Med 1990; 322:1106–12.)
Article Activity
- Article
MANY patients with cancer have hypercalcemia because their tumor produces a humoral factor that interacts with parathyroid hormone receptors.1 2 3 4 5 A novel parathyroid hormone-related protein (PTHRP) has been isolated recently from tumors associated with humoral hypercalcemia of cancer,6 7 8 9 10 its complementary DNA (cDNA) has been cloned, and its gene has been mapped and isolated.11 12 13 14 The PTHRP gene is a complex transcriptional unit that, by alternative splicing, gives rise to messenger RNAs (mRNAs) encoding three related PTHRPs.15 These peptides differ only in their C-terminal regions; all have the same amino acid sequence through residue 139 (Fig. 1Figure 1
Primary Structure of PTHRP.). The amino acid sequence of PTHRP bears striking homology to that of parathyroid hormone from amino acid 1 through amino acid 13, but thereafter it is unique. There are several potential cleavage and amidation sites within the amino acid sequence of PTHRP predicted by cDNA, leading to speculation that the peptide may be subject to post-translational processing or that it may be further modified after it has been secreted into the circulation, or both. In addition to being produced by malignant tumors, PTHRP is found in normal keratinocytes,16 , 17 lactating mammary tissue,18 placenta,19 parathyroid glands,19 , 20 the central nervous system,21 and a number of other sites,20 suggesting that it may have a widespread physiologic role. Little information is available on the circulating forms or concentrations of PTHRP in humoral hypercalcemia of cancer or in other conditions. We report here the results of studies using two new sensitive assays for PTHRP. The findings indicate that plasma PTHRP concentrations are elevated 10-fold in patients with humoral hypercalcemia of cancer as compared with normal subjects; that the majority of patients with cancer and hypercalcemia have humoral hypercalcemia, as determined by measurement of both urinary cyclic AMP excretion and plasma PTHRP; and that both N-terminal and C-terminal fragments of PTHRP, but probably not the intact peptide, circulate in such patients.Methods
Patients
We studied 38 patients with malignant disease and hypercalcemia, 23 with cancer and normal serum calcium levels, 13 with primary hyperparathyroidism (including 2 with parathyroid cancer and 1 with multiple endocrine neoplasia type 2), 4 with hypercalcemia due to miscellaneous causes (sarcoidosis, tuberculosis, and vitamin D intoxication), 3 with hypoparathyroidism (all receiving calcium and vitamin D supplements), 15 with chronic renal failure (all on hemodialysis), and 60 healthy subjects (35 men and 25 women, 22 to 98 years old; mean age, 53). The patients with cancer-associated hypercalcemia were 25 consecutive patients admitted with this diagnosis to the Yale–New Haven Hospital or the West Haven Veterans Affairs Medical Center between January and July 1989, 9 patients from the Memorial Sloan-Kettering Cancer Center, and 4 patients from other hospitals. The majority of these patients had already received some therapy for their hypercalcemia, but all still had hypercalcemia when plasma samples were obtained for the measurement of PTHRP. Of the 38 patients, 30 were classified as having humoral hypercalcemia of cancer and 8 as having local osteolytic hypercalcemia caused by direct skeletal involvement by tumor. The characteristics of these two groups of patients as well as those of the group with cancer and normal serum calcium levels are shown in Table 1Table 1
Clinical and Biochemical Characteristics of the Patients with Cancer.. The following criteria were used to assign patients to the group with humoral hypercalcemia of cancer: elevated urinary excretion of cyclic AMP (25 patients), high-normal urinary excretion of cyclic AMP and squamous-cell or renal carcinoma with minimal skeletal metastatic disease (3 patients), reversal of hypercalcemia after tumor resection and a negative bone scan (1 patient); and islet-cell carcinoma of the pancreas (1 patient). Plasma samples from the last two patients were sent from other hospitals; no urine samples were available from these patients for the assay of cyclic AMP. The extent of skeletal metastatic disease was assessed by radioisotopic bone scanning, computerized tomography, or magnetic resonance imaging in 24 of the 30 patients with humoral hypercalcemia of cancer. Fifteen had negative bone scans and 9 had positive bone scans; in only 1 of these patients was the skeletal involvement extensive. Seven patients were classified as having local osteolytic hypercalcemia on the basis of low urinary excretion of cyclic AMP and extensive skeletal involvement due to breast cancer or multiple myeloma. An eighth patient with multiple myeloma, extensive osteolytic disease, and markedly reduced renal function, in whom urinary cyclic AMP excretion was not measured, was also included in this group.Three patients with humoral hypercalcemia of cancer were studied in more detail. Patient 1 was a 65-year-old man with a 7-cm squamous-cell carcinoma of the left lower lobe of the lung, with no evidence of metastases. The bone scan was negative, the serum calcium level was 2.85 mmol per liter, the urinary cyclic AMP level was elevated (46.1 nmol per liter of glomerular filtrate), and the plasma parathyroid hormone level was low. After the tumor was resected, the serum calcium level decreased within 12 hours to 2.25 mmol per liter; the patient has remained normocalcemic and disease-free. Patient 2 was a 63-year-old man with a previously resected carcinoid tumor of the descending colon in whom hypercalcemia developed (serum calcium level, 3.63 mmol per liter) and a 12-cm carcinoid tumor was found in the left upper quadrant of the abdomen. The bone scan was negative, and the plasma levels of N-terminal and C-terminal parathyroid hormone were low normal. After the tumor was debulked, the serum calcium level decreased to 2.25 mmol per liter, but three weeks later hypercalcemia recurred. Patient 3 was a 42-year-old woman with infiltrating ductal carcinoma of the breast that had metastasized to the liver. The serum calcium level was 2.98 mmol per liter, the urinary cyclic AMP excretion was elevated (55.7 nmol per liter of glomerular filtrate), the plasma parathyroid hormone level was low normal, and the bone scan was negative. After chemotherapeutic agents were administered through the hepatic artery, the enlarged liver decreased markedly in size and became less tender, and the serum calcium level became normal temporarily.
Blood specimens for immunoassay of PTHRP were collected in heparin-treated tubes containing protease inhibitors (aprotinin, 500 klU per milliliter; leupeptin, 5 μg per milliliter; pepstatin, 5 μg per milliliter; and EDTA, 1 mM), immediately placed on ice, and centrifuged; the plasma was stored at −70°C. Serum calcium was measured by atomic absorption, serum creatinine by an automated method, and plasma parathyroid hormone and urinary cyclic AMP by previously described methods.5 , 22 , 23 Breast milk was obtained from five nursing mothers, and bovine pasteurized whole and lowfat milk from commercial sources. All patients and healthy subjects were studied after they had given informed consent according to the guidelines of the Human Investigations Committee at Yale–New Haven Hospital and the Human Studies Committee of the West Haven Veterans Affairs Medical Center.
Peptides and Antiserums
Synthetic Tyr36–PTHRP(1 to 36)amide, PTHRP(1 to 74), PTHRP(37 to 74), and Tyr109–PTHRP(109 to 138) were prepared by solid-phase synthesis as previously described.24 The peptides were conjugated to keyhole limpet hemocyanin, emulsified in Freund's adjuvant, and injected subcutaneously into New Zealand White rabbits. Antiserum R-14, derived from a rabbit immunized with PTHRP(1 to 74), was sufficiently potent that a 1:6000 dilution allowed PTHRP(1 to 74) to be detected by radioimmunoassay at a concentration of 50 pmol per liter. This antiserum was used in the immunoradiometric assay (described below). Antiserum R-22, derived from a rabbit immunized with Tyr109–PTHRP(109 to 138), was used for the direct radioimmunoassay (described below).
Affinity Purification of Antiserums
A PTHRP(1 to 36) immunoaffinity column was prepared by coupling 2 mg of Tyr36–PTHRP(1 to 36)amide to cyanogen bromide—activated Sepharose 4B (Pharmacia, Piscataway, N.J.). Antiserum R-14 was applied to the column, and the antibodies that bound to the immobilized PTHRP(1 to 36) were eluted with glycine—hydrochloride, 200 mmol per liter (pH 2.5). The eluate containing the anti-PTHRP(l to 36) antibodies was neutralized and then Radio-labeled with 125I by a variation of the lactoperoxidase method (Enzymobeads, Bio-Rad Laboratories, Richmond, Calif.).
A PTHRP(1 to 74) immunoaffinity column was prepared by coupling 2 mg of PTHRP(1 to 74) to cyanogen bromide—activated Sepharose 4B. Antiserum R-14 that had passed through the PTHRP(1 to 36) column described above was applied to the PTHRP(1 to 74) column, and antibodies specifically binding to PTHRP( 1 to 74) were eluted. Since the anti-PTHRP(1 to 36) antibodies had been previously immunologically extracted, these eluted antibodies were primarily directed to the C-terminal region of PTHRP(1 to 74) and are referred to as anti-PTHRP(37 to 74) (Fig. 1).
PTHRP(1 to 74) Immunoradiometric Assay
The two-site immunoradiometric assay is a sandwich-type assay in which affinity-purified anti-PTHRP(37 to 74) bound to a solid phase is used as the capture antibody and Radio-labeled anti-PTHRP(l to 36) is used as the signal antibody. Wells of polyvinyl chloride microtiter plates (Dynatech Laboratories, Chantilly, Va.) were filled with 100 μl of affinity-purified anti-PTHRP(37 to 74) in 200 mM borate buffer (pH 8.4) and incubated overnight at 4°C. After washing, the wells were blocked with 300 μl of 1 percent bovine serum albumin in borate buffer for two hours at 25°C and washed again. A sample or an assay standard (200 μl) was added to duplicate wells at 4°C and incubated overnight at 4°C. After washing, 100 μl of Radio-labeled anti-PTHRP(l to 36) in PBT buffer (phosphate-buffered saline, 10 mmol per liter [pH 7.4]–0.1 percent bovine serum albumin-0.1 percent Triton X-100) with 1 percent normal rabbit serum was added to the wells and incubated overnight at 4°C. After a final wash, the wells were counted. As an assay standard, normal human plasma in which PTHRP was not detectable was supplemented with synthetic PTHRP(1 to 74) at concentrations of 0.8, 1.6, 4.0, 8.0, 20, 40, 100, 200, 500, and 1000 pmol per liter. The sensitivity of the immunoradiometric assay to PTHRP(1 to 74) was 1 pmol per liter, and specific binding was proportional to the concentration up to 1000 pmol per liter (Fig. 2Figure 2
Sensitivity and Specificity of Assays for PTHRP.A). The immunoradiometric assay was highly specific for PTHRP(1 to 74), in that PTHRP(1 to 36) was detectable only at concentrations above 1000 pmol per liter (presumably because some anti-PTHRP(l to 36) antibodies were present in the anti-PTHRP(37 to 74) preparation) whereas PTHRP(37 to 74), PTHRP(109 to 138), and hPTH(l to 84) (human parathyroid hormone), in concentrations of up to 100,000 pmol per liter, were undetectable. The intraassay variation averaged 6.6 percent, and the interassay variation was 13.1 percent.One plasma sample from a healthy subject had a very high level of binding in the immunoradiometric assay. This problem was largely alleviated by adding 1 percent normal rabbit serum to the assay (as described above) and was attributed to heterophilic antirabbit IgG antibodies.25 To verify specificity, an anti-PTHRP immunoaffinity column was prepared by covalently coupling affinity-purified anti-PTHRP(l to 36) to protein A–Sepharose CL-4B (Pharmacia), and assay standards were passed through the column; the flow-through (plasma that has passed through the column) contained less than 5 percent of the original PTHRP content, indicating 95 percent extraction. Aliquots of all plasma samples with high binding in the immunoradiometric assay were passed over the column, and the original plasma sample was reassayed together with the flow-through sample. The results are reported as the difference — i.e., the immunoreactivity of the original plasma minus the immunoreactivity of the flow-through fraction. Overall, the flow-through fraction of 11 percent of the samples contained some immunoreactive material, and the results required correction as described above.
PTHRP(109 to 138) Radioimmunoassay
For the radioimmunoassay radioligand, Tyr109–PTHRP(109 to 138) was labeled with 125I according to the Enzymobead method. The sample or assay standard (100 μl) and antiserum R-22 diluted 1:2500 in PBT buffer (100 μl) were incubated in duplicate overnight at 4°C, iodinated PTHRP(109 to 138) with an activity of 2000 cpm in PBT buffer (100 μl) was added, and the tubes were incubated an additional 48 hours at 4°C. Phase separation was accomplished with dextran-coated charcoal, and the radioactivity in both the pellet and supernatant was measured. Nonspecific binding of the [125I]Tyr109–PTHRP(109 to 138) was 5 to 10 percent, and specific binding was 30 to 40 percent in the presence of normal plasma (B0). As an assay standard, normal human plasma containing no detectable PTHRP was supplemented with PTHRP(109 to 138) at concentrations of 1.0, 2.5, 5.0, 10, 25, 50, 100, and 250 pmol per liter. The sensitivity of this PTHRP(109 to 138) assay, indicated by a decrease of 12 percent or more in the specific binding of the sample to the specific binding of the zero standard (B/B0), was 2 pmol per liter, and binding was inhibited completely when the concentration of PTHRP(109 to 138) was 250 pmol per liter. PTHRP(1 to 36), PTHRP(1 to 74), and hPTH(l to 84) in concentrations up to 10,000 pmol per liter did not cross-react in this assay (Fig. 2B). The intraassay variation averaged 9.5 percent, and the interassay variation was 16.4 percent.
Statistical Analysis
The results are given as means ±SD. Descriptive statistics, correlations, and linear regressions were calculated with the program StatView on an Apple Macintosh computer. P values less than 0.05 were considered to indicate statistical significance.
Results
The results of the PTHRP(1 to 74) immunoradiometric assay and the PTHRP(109 to 138) radioimmunoassay are shown in Figure 3Figure 3
Plasma Concentrations of PTHRP(1 to 74) and PTHRP(109 to 138) in the Groups Studied.. Thirty-two of the 60 normal subjects had undetectable levels of PTHRP(1 to 74) (<1 pmol per liter), and 28 had low but detectable levels. When a level of 1 pmol per liter was assigned to the samples in which PTHRP(1 to 74) was undetectable, the mean plasma PTHRP(1 to 74) concentration in the normal subjects was 1.9±1.6 pmol per liter and the upper limit of the normal range (mean +2 SD) was 5.1 pmol per liter. The plasma PTHRP(109 to 138) concentration was undetectable (<2 pmol per liter) in 59 healthy subjects and 2.1 pmol per liter in the 60th.All 30 patients with humoral hypercalcemia of cancer (Table 1) had measurable plasma PTHRP(1 to 74) concentrations, the values ranging from 1.7 to 103 pmol per liter; 25 patients had values above the normal range (Fig. 3A). The mean plasma PTHRP(1 to 74) concentration in these 30 patients was 20.9±21.8 pmol per liter, more than 10 times the normal mean. All 30 patients with humoral hypercalcemia of cancer had levels of PTHRP(109 to 138) above the normal range; the mean plasma PTHRP(109 to 138) concentration was 23.9±16.0 pmol per liter, ranging from 2.1 to 74 pmol per liter (Fig. 3B). In contrast to the patients with humoral hypercalcemia of cancer, the eight patients with local osteolytic hypercalcemia (Table 1) all had normal plasma PTHRP(1 to 74) levels. Five of the eight (two of whom had renal insufficiency and serum creatinine concentrations of 260 and 860 μmol per liter) had moderately elevated PTHRP(109 to 138) levels (Fig. 3B).
Of the 23 patients with cancer and normal serum calcium levels, 74 percent had detectable plasma PTHRP(1 to 74) concentrations. The mean plasma PTHRP(1 to 74) level was 2.8±2.3 pmol per liter, and two patients had levels above the normal range. Six of these 23 patients had elevated plasma PTHRP(109 to 138) levels. Two of these patients (represented by triangles in Figure 3) had squamouscell carcinomas, and hypercalcemia subsequently developed in both.
All 13 patients with primary hyperparathyroidism had plasma PTHRP(1 to 74) levels within the normal range (mean, 1.8±1.4 pmol per liter). All but one had undetectable levels of PTHRP(109 to 138). Two patients with primary hyperparathyroidism from whom blood samples were obtained during surgery had no gradient of PTHRP between the neck vein and peripheral vein, as found on assay of plasma samples from these sites. The four patients with miscellaneous causes of hypercalcemia and the three treated patients with hypoparathyroidism also had normal plasma PTHRP levels in both assays.
All but 1 of 15 patients with chronic renal failure had normal plasma PTHRP(1 to 74) concentrations. In contrast, all 15 had markedly elevated plasma PTHRP(109 to 138) levels (Fig. 3); the mean was 29.6±14.1 pmol per liter, comparable to the mean level in the patients with humoral hypercalcemia of cancer.
Both bovine and human milk contained strikingly high concentrations of PTHRP(1 to 74) (mean, 35,100±22,800 pmol per liter). In the immunoradiometric assay, the immunoreactivity of serial dilutions of milk in normal plasma decreased in parallel with the immunoreactivity of the PTHRP(1 to 74) standard. Milk caused interference in [125I]Tyr109–PTHRP (109 to 138) binding in the PTHRP(109 to 138) radioimmunoassay, making precise quantification difficult in this assay. However, when diluted at least 1:50 in plasma, human milk contained immunoreactivity that decreased in serial dilutions in parallel with that of the PTHRP(109 to 138) standard. Human milk was estimated to have lower concentrations of PTHRP(109 to 138) (mean, 1990±460 pmol per liter) than of PTHRP(1 to 74); bovine milk had undetectable levels of PTHRP(109 to 138).
Urinary cyclic AMP excretion was determined in 35 of the 38 patients with cancer-associated hypercalcemia. There was a strongly positive correlation between the plasma PTHRP( 1 to 74) concentration and urinary cyclic AMP excretion in these patients (R = 0.52, P<0.002) (Fig. 4Figure 4
Plasma PTHRP(1 to 74) Concentration in Relation to Urinary Excretion of Cyclic AMP in 35 Patients with Cancer-Associated Hypercalcemia.). Similarly, there was a positive correlation between the plasma PTHRP(109 to 138) concentration and cyclic AMP excretion (R = 0.57, P<0.001) and between the plasma concentrations of PTHRP(109 to 138) and PTHRP(1 to 74) (R = 0.34, P<0.05). Among the 30 patients with humoral hypercalcemia of cancer, there was no correlation between either the plasma level of PTHRP(1 to 74) or PTHRP(109 to 138) and the serum calcium level.Three patients with humoral hypercalcemia of cancer (described under Methods) were studied in more detail. Patient 1 underwent curative resection of a lung tumor. At surgery, the PTHRP(1 to 74) level in peripheral venous plasma was 7.6 pmol per liter, and the level in tumor venous plasma was 30 pmol per liter. Postoperatively, the serum calcium level became normal and the plasma PTHRP(1 to 74) level became undetectable. Patient 2 underwent debulking of a carcinoid tumor. At surgery, the PTHRP(1 to 74) level in peripheral plasma was 44 pmol per liter, and the level in tumor venous plasma was 550 pmol per liter. Postoperatively, the serum calcium level was normal and the plasma PTHRP(1 to 74) level decreased to 1.6 pmol per liter. However, three weeks later hypercalcemia recurred; at this time the plasma PTHRP(1 to 74) level was 25 pmol per liter. Patient 3 had hypercalcemia that was caused by a breast carcinoma, with an elevated plasma PTHRP(1 to 74) level (53 pmol per liter). Shortly after intrahepatic administration of chemotherapy the liver metastases regressed, the serum calcium level fell to normal, and the plasma PTHRP(1 to 74) level fell to 10.0 pmol per liter.
The results obtained in the two immunoassays indicated that both PTHRP(1 to 74) and PTHRP(109 to 138) determinants were present in the plasma of patients with humoral hypercalcemia of cancer. To determine whether this immunoreactivity resulted from the presence of "intact" PTHRP or from the circulation of separate N-terminal and C-terminal fragments of PTHRP, plasma samples from 15 patients with the disorder were immunologically extracted with the use of the anti-PTHRP(l to 36) antibody column. The flow-through from this column was assayed in both the PTHRP(1 to 74) immunoradiometric assay and the PTHRP(109 to 138) radioimmunoassay. Although PTHRP(1 to 74) immunoreactivity was completely extracted with this technique, the PTHRP(109 to 138) levels in the column flow-through (mean, 37.0 pmol per liter) were nearly identical to those in the original plasma sample (mean, 36.2 pmol per liter). Since it is possible that anti-PTHRP(l to 36) may not recognize intact PTHRP, the presence of intact PTHRP could not be excluded. However, the failure of the anti-PTHRP(1 to 36) column to extract PTHRP(109 to 138) immunoreactivity suggests that intact PTHRP was not present in the plasma of patients with humoral hypercalcemia of cancer.
Discussion
We found elevated plasma PTHRP concentrations in the majority of patients with hypercalcemia and cancer. The occasional resolution of hypercalcemia after tumor resection,26 the recent isolation of PTHRP from tumors associated with humoral hypercalcemia of cancer,6 7 8 9 10 evidence that synthetic PTHRP interacts with parathyroid hormone receptors and can cause hypercalcemia when infused into animals,24 , 27 28 29 30 31 and a report that anti-PTHRP antibodies can reverse humoral hypercalcemia of cancer in rodents32 all support a fundamental role for tumor secretion of PTHRP in the pathogenesis of humoral hypercalcemia of cancer. Until recently,33 , 34 however, direct documentation of elevated plasma PTHRP concentrations in patients with this disorder was lacking. In this study we found that in patients defined independently as having humoral hypercalcemia of cancer, plasma PTHRP(1 to 74) levels were 10-fold higher than those in healthy subjects. The measured plasma concentrations were consistent with previous estimates based on cytochemical bioassay2 and comparable to concentrations of PTHRP(1 to 34) recently found by radioimmunoassay of serum extracts.33 In addition, we found that plasma PTHRP(109 to 138) levels were elevated 10-fold above normal in the same patients with humoral hypercalcemia of cancer.
In most patients with cancer-associated hypercalcemia, the hypercalcemia appears to have a humoral basis.1 , 5 In our series of patients, the majority (approximately 80 percent) had both biochemical evidence (i.e., elevated urinary cyclic AMP excretion) and immunologic evidence of humoral hypercalcemia of cancer. These patients included not only those with squamous, renal, and urothelial carcinomas but also many with other tumors, including breast carcinoma, adenocarcinoma, and lymphoma. Although the hypercalcemia of women with breast cancer has traditionally been considered to be caused by local osteolytic skeletal mechanisms, evidence is accumulating that humoral mechanisms may be an equally common cause of hypercalcemia in such patients.35 Three of seven unselected patients with breast cancer in this series had clinical, biochemical, and immunologic evidence of humoral hypercalcemia of cancer and few or no skeletal metastases.
Increased urinary cyclic AMP excretion serves as a marker for the humoral hypercalcemia of cancer syndrome1 , 5 — an observation that led to the use of assays for parathyroid hormone—sensitive adenylate cyclase for the identification and purification of PTHRP.6 7 8 9 10 One would thus expect a correlation between the plasma PTHRP level and urinary cyclic AMP excretion. Such a correlation was found for both plasma PTHRP(1 to 74) and PTHRP(109 to 138), suggesting that concentrations of immunoreactive PTHRP are related causally to increased urinary cyclic AMP excretion and to the humoral hypercalcemia of cancer syndrome. The correlation between plasma PTHRP and serum calcium concentrations was not significant in the patients we studied, presumably reflecting variations in hydration and previous antihypercalcemic therapy among the patients.
In the normocalcemic patients with cancer, the mean plasma PTHRP(1 to 74) and PTHRP(109 to 138) concentrations were slightly elevated; in some patients the levels were above the normal range. Two of these patients, who had squamous-cell carcinomas and elevated PTHRP levels, although normocalcemic at the time of PTHRP measurement, later became hypercalcemic. In three patients with humoral hypercalcemia of cancer, plasma PTHRP concentrations decreased after surgical or chemotherapeutic treatment of the tumor. These observations suggest that in selected patients, PTHRP assays may prove to be a useful marker of tumor burden, response to therapy, or tumor recurrence.
Renal failure was associated with a 10-fold elevation in plasma PTHRP(109 to 138) levels, but with normal PTHRP(1 to 74) levels. These results suggest that PTHRP enters the circulation in patients without cancer, and that a C-terminal fragment (or fragments) that is cleared by the kidneys may accumulate when renal failure is present.
PTHRP mRNA has been detected at sites as diverse as skin,16 the central nervous system,21 lactating mammary glands,18 and parathyroid adenomas.20 Since most of these sites are not involved in calcium homeostasis, it is thought that PTHRPs may have autocrine or paracrine functions in these tissues. However, since PTHRP mRNA is expressed in parathyroid adenomas, the question arises whether circulating PTHRP contributes to the pathophysiology of hyperparathyroidism. We studied 13 patients with hyperparathyroidism and found normal plasma PTHRP levels in all. In addition, two patients undergoing surgical removal of parathyroid adenomas had similar PTHRP concentrations in plasma samples from the neck vein and peripheral vein. These results, although they do not support a role for PTHRP in the hypercalcemia of hyperparathyroidism, underscore the specificity of PTHRP elevations for humoral hypercalcemia of cancer.
Mammary tissue18 and milk36 have recently been reported to contain PTHRP. We found high levels of PTHRP(1 to 74) in both human breast milk and pasteurized bovine milk, in which the concentrations were approximately 1000 times higher than the plasma levels found in patients with humoral hypercalcemia of cancer. In addition, PTHRP(109 to 138) was also detected in human milk, but perhaps because of differences between species in the C-terminal amino acid sequence,37 it was not detected in bovine milk.
Although the amino acid sequences of three PTHRPs as predicted by mRNA are known11 12 13 14 15 (Fig. 1), the circulating forms of PTHRP have not been characterized. The biologic activity of PTHRP has been ascribed primarily to the first 34 amino acids of the N terminus,28 29 30 31 and the physiologic function of the unique C-terminal sequence, if any, is unknown. Previous cytochemical and immunologic evidence for circulating PTHRP in patients with humoral hypercalcemia of cancer has been limited to the recognition of the initial N-terminal region.2 , 33 , 34 In the present study, we found immunologic evidence for the presence of considerably larger regions of the protein in the plasma of the patients with this disorder. Although the precise specificities of the affinity-purified anti-PTHRP(l to 36) and anti-PTHRP(37 to 74) antibodies are unknown, the N-terminal fragment (or fragments) detected by the PTHRP(1 to 74) immunoradiometric assay is presumably substantially larger than that of PTHRP(1 to 36). In addition, we found approximately equimolar elevations of the levels of a C-terminal fragment, using the PTHRP(109 to 138) radioimmunoassay. The evidence against the presence of "intact" PTHRP in plasma is particularly noteworthy. The abundance of potential proteolytic sites in the 88 to 108 region of PTHRP (Fig. 1) is consistent with the existence of separate N-terminal and C-terminal fragments.
In summary, using two region-specific immunoassays, we found elevated plasma levels of a large N-terminal fragment and a C-terminal fragment of PTHRP in the majority of patients with cancer-associated hypercalcemia. Elevated plasma PTHRP(1 to 74) concentrations appear to be specific for the humoral hypercalcemia of cancer syndrome, whereas plasma PTHRP(109 to 138) was elevated in both patients with this disorder and patients with renal failure. These assays should be clinically useful in the differential diagnosis of hypercalcemia.
Supported by the Department of Veterans Affairs (West Haven), by grants (AR-30102 and CA-42445) from the National Institutes of Health, and by a grant (RR-125) to the Yale–New Haven Hospital Adult Clinical Research Center.
We are indebted to Drs. Roberto Calle, Greg Gerety, Barbara Kinder, Bruce Lundberg, John Machledt, and Louis Tellesford, as well as Ms. Alice Ellison, Ms. Marianne Frisone, Ms. Theresa Snyder, and the staffs of the Yale–New Haven Hospital Clinical Research Center, the Yale–New Haven Hospital Oncology Clinic, and the West Haven Veterans Affairs Medical Center Dialysis Unit for their assistance in collecting specimens from the patients; and to Mrs. Ann Blood and Ms. Kristie Vollono for assistance in the preparation of the manuscript.
Source Information
From the Department of Medicine, West Haven Veterans Affairs Medical Center, West Haven, Conn. (W.J.B., T.G.B., J.J.O., J.B.E., A.F.S.); Yale University School of Medicine, New Haven, Conn. (W.J.B., J.J.O., T.L.W., M.E.M., A.E.B., A.F.S.); Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York (R.P.W.); and the University of Pittsburgh School of Medicine, Pittsburgh (B.R.O.). Address reprint requests to Dr. Burtis at Research/151, West Haven Veterans Affairs Medical Center, 950 Campbell Ave., West Haven, CT 06516.
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- Citing Articles (147)
Citing Articles
1
Patricia A. Schenck, Dennis J. Chew, Larry A. Nagode, Thomas J. Rosol. 2012. Disorders of Calcium. , 120-194.
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Christian A. Waimann, Huifang Lu, Maria E. Suarez Almazor. (2011) Rheumatic Manifestations of Primary and Metastatic Bone Tumors and Paraneoplastic Bone Disease. Rheumatic Disease Clinics of North America
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Anna Milanesi, Run Yu, Stephen A. Geller, Doug Burton, Leonard J. Deftos, Edward M. Wolin. (2011) Concurrent Primary Hyperparathyroidism and Humoral Hypercalcemia of Malignancy in a Patient With Multiple Endocrine Neoplasia Type 1. Pancreas 40:4, 634-637
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Larry J. Suva, Charity Washam, Richard W. Nicholas, Robert J. Griffin. (2011) Bone metastasis: mechanisms and therapeutic opportunities. Nature Reviews Endocrinology 7:4, 208-218
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Harald Jüppner, John T. Jr. Potts. 2011. Roles of Parathyroid Hormone and Parathyroid Hormone-Related Peptide in Calcium Metabolism and Bone Biology: Biological Actions and Receptors. .
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Elizabeth Holt, John J. Wysolmerski. 2011. Parathyroid Hormone, Parathyroid Hormone-Related Protein, and Calcitonin. , 725-745.
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Yoshiaki Onodera, Yasuhiro Miki, Takashi Suzuki, Kiyoshi Takagi, Jun-ichi Akahira, Takuya Sakyu, Mika Watanabe, Satoshi Inoue, Takanori Ishida, Noriaki Ohuchi, Hironobu Sasano. (2010) Runx2 in human breast carcinoma: its potential roles in cancer progression. Cancer Science 101:12, 2670-2675
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Shin-ichi Yamada, Souichi Yanamoto, Goro Kawasaki, Akio Mizuno, Takayuki K. Nemoto. (2010) Overexpression of Cortactin Increases Invasion Potential in Oral Squamous Cell Carcinoma. Pathology & Oncology Research 16:4, 523-531
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Akihiro Asakawa, Mineko Fujimiya, Akira Niijima, Kazunori Fujino, Noriko Kodama, Yuki Sato, Ikuo Kato, Hiroaki Nanba, Alessandro Laviano, Michael M. Meguid, Akio Inui. (2010) Parathyroid hormone-related protein has an anorexigenic activity via activation of hypothalamic urocortins 2 and 3. Psychoneuroendocrinology 35:8, 1178-1186
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Martin N. Montoro, T. Murphy Goodwin. 2010. Calcium Metabolism and Diseases of the Parathyroid Glands during Pregnancy. , 352-370.
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Constantinos H. Houpis, Konstantinos I. Tosios, Dimitrios Papavasileiou, Panagiotis G. Christopoulos, Ioannis G. Koutlas, Alexandra Sklavounou, Constantinos Alexandridis. (2010) Parathyroid hormone–related peptide (PTHrP), parathyroid hormone/parathyroid hormone–related peptide receptor 1 (PTHR1), and MSX1 protein are expressed in central and peripheral giant cell granulomas of the jaws. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 109:3, 415-424
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A. G. Gow, D. J. Gow, R. Bell, J. W. Simpson, M. L. Chandler, H. Evans, J. L. Berry, M. E. Herrtage, R. J. Mellanby. (2009) Calcium metabolism in eight dogs with hypoadrenocorticism. Journal of Small Animal Practice 50:8, 426-430
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M.H. Vieillard, I. Gerot-Legroux, B. Cortet. (2009) Hipercalcemia del adulto. EMC - Aparato Locomotor 42:4, 1-10
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Yoshiya Hosokawa, Yuya Yamada, Ryuya Iwamoto, Rie Kurokawa, Arisa Ihara, Koji Yamamoto, Katsuhiko Sakaguchi, Shin-ichi Nakatsuka, Yuzo Minami, Yuji Matsuzawa. (2009) Thyroid Follicular Adenoma Producing Parathyroid Hormone-related Protein with a Normal Serum Calcium Level. Internal Medicine 48:22, 1957-1961
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Tamaki Yamada, Masumi Tsuda, Yusuke Ohba, Hideaki Kawaguchi, Yasunori Totsuka, Masanobu Shindoh. (2008) PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling. Biochemical and Biophysical Research Communications 368:3, 575-581
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Antonella De Luca, Adele Carotenuto, Annamaria Rachiglio, Marianna Gallo, Monica R. Maiello, Donatella Aldinucci, Antonio Pinto, Nicola Normanno. (2008) The role of the EGFR signaling in tumor microenvironment. Journal of Cellular Physiology 214:3, 559-567
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D. Razavi, M. Reich, D. Lossignol, N. Delvaux. 2008. Troubles mentaux organiques. , 143-164.
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Gert G. Van den Eynden, Aymeric Neyret, Glawdys Fumey, Marthe Rizk-Rabin, Peter B. Vermeulen, Zhor Bouizar, Jean-Jacques Body, Luc Y. Dirix. (2007) PTHrP, calcitonin and calcitriol in a case of severe, protracted and refractory hypercalcemia due to a pancreatic neuroendocrine tumor. Bone 40:4, 1166-1171
CrossRef19
T Inukai, K Hirose, T Inaba, H Kurosawa, A Hama, H Inada, M Chin, Y Nagatoshi, Y Ohtsuka, M Oda, H Goto, M Endo, A Morimoto, M Imaizumi, N Kawamura, Y Miyajima, M Ohtake, R Miyaji, M Saito, A Tawa, F Yanai, K Goi, S Nakazawa, K Sugita. (2007) Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19. Leukemia 21:2, 288-296
CrossRef20
Muzaffer Cicek, Merry Jo Oursler. (2007) Breast cancer bone metastasis and current small therapeutics. Cancer and Metastasis Reviews 25:4, 635-644
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Yasuharu Tokuda, Kyouko Maezato, Gerald H. Stein. (2007) The Causes of Hypercalcemia in Okinawan Patients: AnInternational Comparison. Internal Medicine 46:1, 23-28
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C Cooper Worobey, C C Magee. (2006) Humoral hypercalcemia of malignancy presenting after oncologic surgery. Kidney International 70:1, 225-229
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Govinda Pillai Arumugam, Sengoden Sundravel, Palanivel Shanthi, Panchanadham Sachdanandam. (2006) Tamoxifen flare hypercalcemia: an additional support for gallium nitrate usage. Journal of Bone and Mineral Metabolism 24:3, 243-247
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E. J. Raubenheimer, C. E. E. Noffke. (2006) Pathogenesis of bone metastasis: a review. Journal of Oral Pathology and Medicine 35:3, 129-135
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Xiangtao Ma, Xu Wang, Liwei Yu, Jing Fu, Shan Wang, Ruyu Du, Zhirong Cui. (2006) Paraneoplastic syndromes of hypercalcemia and leukocytosis associated with colonic metastases from squamous cell carcinoma of the lung: a case report. Chinese Journal of Clinical Oncology 3:1, 66-69
CrossRef26
Patricia A. Schenck, Dennis J. Chew, Larry Allen Nagode, Thomas J. Rosol. 2006. Disorders of Calcium: Hypercalcemia and Hypocalcemia. , 122-194.
CrossRef27
Mara J Horwitz, Mary Beth Tedesco, Susan M Sereika, Mushtaq A Syed, Adolfo Garcia-Ocaña, Alessandro Bisello, Bruce W Hollis, Clifford J Rosen, John J Wysolmerski, Pamela Dann, Caren Gundberg, Andrew F Stewart. (2005) Continuous PTH and PTHrP Infusion Causes Suppression of Bone Formation and Discordant Effects on 1,25(OH)2Vitamin D. Journal of Bone and Mineral Research 20:10, 1792-1803
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Makoto Tsuchimochi, Ayako Kameta, Mikiko Sue, Masataka Katagiri. (2005) Immunohistochemical localization of parathyroid hormone-related protein (PTHrP) and serum PTHrP in normocalcemic patients with oral squamous cell carcinoma. Odontology 93:1, 61-71
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L. Anjos, J. Rotllant, P.M. Guerreiro, X. Hang, A.V.M. Canario, R. Balment, D.M. Power. (2005) Production and characterisation of gilthead sea bream (Sparus auratus) recombinant parathyroid hormone related protein. General and Comparative Endocrinology 143:1, 57-65
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Kohtaroh Tanaka, Ken-ichi Nibu. (2005) Laryngeal squamous cell carcinoma with ectopic production of granulocyte colony-stimulating factor and parathyroid hormone-related protein. International Journal of Clinical Oncology 10:3, 195-197
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Wende Kozlow, Theresa A. Guise. (2005) Breast Cancer Metastasis to Bone: Mechanisms of Osteolysis and Implications for Therapy. Journal of Mammary Gland Biology and Neoplasia 10:2, 169-180
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Karin Papworth, Kjell Grankvist, Börje Ljungberg, Torgny Rasmuson. (2005) Parathyroid Hormone-Related Protein and Serum Calcium in Patients with Renal Cell Carcinoma. Tumor Biology 26:4, 201-206
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Randolph H. Hastings. (2004) Parathyroid hormone-related protein and lung biology. Respiratory Physiology & Neurobiology 142:2-3, 95-113
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Ahmet Bilici, Alper Doventas, Berrin Karadag, Nezih Hekim, Vecdet Tezcan. (2004) Hypercalcemia associated with a uterine leiomyoma: a case report and review of the literature. Gynecologic Oncology 93:1, 269-271
CrossRef35
Akio Hiraki, Hiroshi Ueoka, Ichiro Takata, Kenichi Gemba, Akihiro Bessho, Yoshihiko Segawa, Katsuyuki Kiura, Kenji Eguchi, Toshiyuki Yoneda, Mitsune Tanimoto, Mine Harada. (2004) Hypercalcemia–leukocytosis syndrome associated with lung cancer. Lung Cancer 43:3, 301-307
CrossRef36
Fumiaki YOSHIIKE, Tomonobu KOIZUMI, Ayako YONEYAMA, Michiharu KOMATU, Shinji YAMAGUCHI, Masayuki HANAOKA, Keishi KUBO, Seiichirou EDA. (2004) Thymic Squamous Cell Carcinoma Producing Parathyroid Hormone-related Protein and CYFRA 21-1. Internal Medicine 43:6, 493-495
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Peter J. Mazzone, Alejandro C. Arroliga. (2003) Endocrine paraneoplastic syndromes in lung cancer. Current Opinion in Pulmonary Medicine 9:4, 313-320
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Peter Attia, Giao Q. Phan, Paul H. Duray, Steven A. Rosenberg. (2003) Parathyroid Hormone-Related Protein and Hypercalcemia in Patients With Metastatic Melanoma. American Journal of Clinical Oncology 26:1, 42-45
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Wolfgang E. Gallwitz, Theresa A. Guise, Gregory R. Mundy. (2002) Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo. Journal of Clinical Investigation 110:10, 1559-1572
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K Mekaapiruk. (2002) The influence of parathyroid hormone-related protein (PTHrP) on tooth-germ development and osteoclastogenesis in alveolar bone of PTHrP-knock out and wild-type mice in vitro. Archives of Oral Biology 47:9, 665-672
CrossRef41
John J. Wysolmerski, Pamela R. Dann, Edward Zelazny, Maureen E. Dunbar, Karl L. Insogna, Theresa A. Guise, Archibald S. Perkins. (2002) Overexpression of Parathyroid Hormone-Related Protein Causes Hypercalcemia but Not Bone Metastases in a Murine Model of Mammary Tumorigenesis. Journal of Bone and Mineral Research 17:7, 1164-1170
CrossRef42
T.A Guise, J.J Yin, R.J Thomas, M Dallas, Y Cui, M.T Gillespie. (2002) Parathyroid hormone-related protein (PTHrP)-(1-139) isoform is efficiently secreted in vitro and enhances breast cancer metastasis to bone in vivo. Bone 30:5, 670-676
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R.S. Sellers, C.C. Capen, Thomas J. Rosol. (2002) Messenger RNA stability of parathyroid hormone-related protein regulated by transforming growth factor-β1. Molecular and Cellular Endocrinology 188:1-2, 37-46
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Megumi Fujikawa, Yutaka Takata, Ken Okamura, Mizuho Nakagawa, Akira Tateishi, Hideo Kurokawa, Kaori Sato, Jinichi Fukuda, Minoru Kajiyama, Masatoshi Fujishima. (2002) Hypercalcemia associated with parathyroid hormone-related protein at the terminal stage of uncomplicated squamous cell carcinoma in the head and neck region. Head & Neck 24:1, 56-62
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S. Radhakrishnan, S. Haq, F. Lofts, M.P.A. Young, D.P.J. Barton. (2001) Ovarian dysgerminoma presenting with hypercalcaemia. BJOG: An International Journal of Obstetrics and Gynaecology 108:12, 1302-1304
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Munehisa Ueno, Masumi Akita, Shin-ichi Ban, Takashi Ohigashi, Saori Yanagita, Masahiro Iida, Nobuhiro Deguchi. (2001) Production of parathyroid hormone-related protein in two new cell lines of renal cell carcinoma. International Journal of Urology 8:10, 549-556
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Randolph H. Hastings, Douglas W. Burton, Rick A. Quintana, Elana Biederman, Aneeta Gujral, Leonard J. Deftos. (2001) Parathyroid hormone-related protein regulates the growth of orthotopic human lung tumors in athymic mice. Cancer 92:6, 1402-1410
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A Lortholary. (2001) Hypercalcémies tumorales. Actualités sur le traitement par les bisphosphonates. La Revue de Médecine Interne 22:7, 648-652
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M KAPOOR, G CHAN. (2001) FLUID AND ELECTROLYTE ABNORMALITIES. Critical Care Clinics 17:3, 503-529
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Kyousuke Takeuchi, Kazuo Murata, Kaoru Funaki, Souhei Kitazawa, Riko Kitazawa. (2000) Immunohistochemical Detection of Parathyroid Hormone-Related Protein in a Squamous Cell Carcinoma Arising from Mature Cystic Teratoma Causing Humoral Hypercalcemia of Malignancy. Gynecologic Oncology 79:3, 504-507
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Yoshiki Uemura, Hideshi Nakata, Makoto Kobayashi, Ryuji Harada, Yasutomo Asahi, Hirokuni Taguchi. (2000) Regulation of Granulocyte Colony-stimulating Factor and Parathyroid Hormonerelated Protein Production in Lung Carcinoma Cell Line OKa-C-1. Cancer Science 91:9, 911-917
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Gordon J. Strewler. (2000) THE PARATHYROID HORMONE–RELATED PROTEIN. Endocrinology & Metabolism Clinics of North America 29:3, 629-645
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Theresa A. Guise. (2000) Molecular mechanisms of osteolytic bone metastases. Cancer 88:S12, 2892-2898
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Yoshinobu Matsuo, Hans G. Drexler, Chiharu Nishizaki, Akira Harashima, Shunichi Fukuda, Teruhiko Kozuka, Tatsuo Sezaki, Kunzo Orita. (2000) Human bone marrow stroma-dependent cell line MOLP-5 derived from a patient in leukaemic phase of multiple myeloma. British Journal of Haematology 109:1, 54-63
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Haiqin Rong, Hong Ji, Jon A. Tsai, Ylva Pernow, Elisabet Bucht. (1999) Calcitonin-Suppressed Expression of Parathyroid Hormone-Related Protein in Breast Cancer Cells. Biochemical and Biophysical Research Communications 265:1, 260-264
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Eric A.G. Blomme, Yasuro Sugimoto, Young C. Lin, Charles C. Capen, Thomas J. Rosol. (1999) Parathyroid hormone-related protein is a positive regulator of keratinocyte growth factor expression by normal dermal fibroblasts. Molecular and Cellular Endocrinology 152:1-2, 189-197
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Juan Juan Yin, Katri Selander, John M. Chirgwin, Mark Dallas, Barry G. Grubbs, Rotraud Wieser, Joan Massagué, Gregory R. Mundy, Theresa A. Guise. (1999) TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. Journal of Clinical Investigation 103:2, 197-206
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F de Miguel, J.L Motellón, J Hurtado, F.J Jiménez, P Esbrit. (1998) Comparison of two immunoradiometric assays for parathyroid hormone-related protein in the evaluation of cancer patients with and without hypercalcemia. Clinica Chimica Acta 277:2, 171-180
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Minoru Ohmori, Masami Nagai, Mitsuhiro Fujita, Hiroaki Dobashi, Taizo Tasaka, Genji Yamaoka, Koichi Kawanishi, Masafumi Taniwaki, Jiro Takahara. (1998) A novel mature B-cell line (DOBIL-6) producing both parathyroid hormone-related protein and interleukin-6 from a myeloma patient presenting with hypercalcaemia. British Journal of Haematology 101:4, 688-693
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Guan Wu, Masatsugu Iwamura, P.Anthony Di Sant’agnese, Leonard J. Deftos, Abraham T.K. Cockett, Sten Gershagen. (1998) Characterization of the cell-specific expression of parathyroid hormone–related protein in normal and neoplastic prostate tissue. Urology 51:5, 110-120
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Steven D. Heys, Ian C. Smith, Oleg Eremin. (1998) Hypercalcaemia in patients with cancer: aetiology and treatment. European Journal of Surgical Oncology (EJSO) 24:2, 139-142
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V Grill, W Rankin, T.J Martin. (1998) Parathyroid hormone-related protein (PTHrP) and hypercalcaemia. European Journal of Cancer 34:2, 222-229
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Mordechai Weiss, Zemach Eisenstein, Yoram Ramot, Shlomo Lipitz, Adrian Shulman, Yair Frenkel. (1998) Renal reabsorption of inorganic phosphorus in pregnancy in relation to the calciotropic hormones. BJOG: An International Journal of Obstetrics and Gynaecology 105:2, 195-199
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Raymond P. Warrell. (1997) Gallium nitrate for the treatment of bone metastases. Cancer 80:S8, 1680-1685
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Wayne Rankin, Vivian Grill, T. John Martin. (1997) Parathyroid hormone-related protein and hypercalcemia. Cancer 80:S8, 1564-1571
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Theresa A. Guise. (1997) Parathyroid hormone-related protein and bone metastases. Cancer 80:S8, 1572-1580
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Elizabeth Shane, May Parisien, Janet E. Henderson, David W. Dempster, Frieda Feldman, Mark A. Hardy, Jack F. Tohme, Andrew C. Karaplis, Thomas L. Clemens. (1997) Tumor-Induced Osteomalacia: Clinical and Basic Studies. Journal of Bone and Mineral Research 12:9, 1502-1511
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McClellan M. Walther, Biren Patel, Peter L. Choyke, Irina A. Lubensky, Cathy D. Vocke, Cynthia Harris, David Venzon, William J. Burtis, W. Marston Linehan. (1997) Hypercalcemia in Patients With Metastatic Renal Cell Carcinoma: Effect of Nephrectomy and Metabolic Evaluation. The Journal of Urology 158:3, 733-739
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Toshiyuki Yasui, Hirokazu Uemura, Minoru Irahara, Toshihiro Aono. (1997) Effects of Transforming Growth Factor-β on the Production of Parathyroid Hormone-Related Peptide in a Human Ovarian Cancer Cell Line in vitro. Asia-Oceania Journal of Obstetrics and Gynaecology 23:3, 231-238
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Ellen W. Seely, Edward M. Brown, Derna M. DeMaggio, Dale K. Weldon, Steven W. Graves. (1997) A prospective study of calciotropic hormones in pregnancy and post partum: Reciprocal changes in serum intact parathyroid hormone and 1,25-dihydroxyvitamin D. American Journal of Obstetrics and Gynecology 176:1, 214-217
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Leonard J. Deftos, Douglas W. Burton, Stephen M. Baird, Robert A. Terkeltaub. (1996) Hypercalcemia and systemic lupus erythematosus. Arthritis & Rheumatism 39:12, 2066-2069
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Thierry Massfelder, Andrew F Stewart, Karlhans Endlich, Neil Soifer, Clément Judes, Jean-Jacques Helwig. (1996) Parathyroid hormone-related protein detection and interaction with NO and cyclic AMP in the renovascular system. Kidney International 50:5, 1591-1603
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Eiji Takai, Tokujiro Yano, Haruo Iguchi, Yasuro Fukuyama, Hideki Yokoyama, Hiroshi Asoh, Yukito Ichinose. (1996) Tumor-induced hypercalcemia and parathyroid hormone-related protein in lung carcinoma. Cancer 78:7, 1384-1387
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SATORU OHOISHI, TATUO KOSHIBU, HIROMI KAZAMA, NORIAKI SHINOMIYA, TUGUTOSHI AOKI. (1996) Common acute lymphoblastic leukemia preceded by hypercalcemia in an infant. Pediatrics International 38:5, 549-552
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Yousri M. Barri, James P. Knochel. (1996) HYPERCALCEMIA AND ELECTROLYTE DISTURBANCES IN MALIGNANCY. Hematology/Oncology Clinics of North America 10:4, 775-790
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Yasutomo Asahi, Ichiro Kubonishi, Jun Imamura, Mikio Kamioka, Hiroshi Matsushita, Mutsuo Furihata, Yuji Ohtsuki, Isao Miyoshi. (1996) Establishment of a Clonal Cell Line Producing Granulocyte Colony-Stimulating Factor and Parathyroid Hormone-Related Protein from a Lung Cancer Patient with Leukocytosis and Hypercalcemia. Cancer Science 87:5, 451-458
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Mutsuo Furlhata, Hiroshi Sonobe, Jun Iwata, Eiji Ido, Yuji Ohtsukl, Yasutomo Asahi, Ichiro Kubonishl, Isao Miyoshi. (1996) Lung squamous cell carcinoma producing both parathyroid hormone-related peptide and granulocyte colony stimulating factor. Pathology International 46:5, 376-379
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T. Schilling, M. Pecherstorfer, E. Blind, B. Kohl, H. Wagner, R. Ziegler, F. Raue. (1996) Glucocorticoids decrease the production of parathyroid hormone-related protein in vitro but not in vivo in the walker carcinosarcoma 256 rat model. Bone 18:4, 315-319
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MASACHIKA SENBA, MIKIYO I. SENBA. (1996) Acute pancreatitis associated with hypercalcaemia in adult T-cell leukaemia-lymphoma. Journal of Gastroenterology and Hepatology 11:2, 180-182
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A. Segura Domínguez, M.A. Andrade Olivié, T. Rodríguez Sousa, M.L. Terrón Alvarez, D. Rodríguez Perez, R. Alvarez Novoa, R.G.V. García-Mayor. (1996) Plasma parathyroid hormone related-protein levels in patients with cancer, normocalcemic and hypercalcemic. Clinica Chimica Acta 244:2, 163-172
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R.Paul Robertson. (1995) Molecular regulation of prostaglandin synthesis. Trends in Endocrinology & Metabolism 6:9-10, 293-297
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Claudio Luparello, William J Burtis, Friedhelm Raue, Mark A. Birch, James A. Gallagher. (1995) Parathyroid hormone-related peptide and 8701-BC breast cancer cell growth and invasion in vitro: evidence for growth-inhibiting and invasion-promoting effects. Molecular and Cellular Endocrinology 111:2, 225-232
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Thomas J. Rosol, Dennis J. Chew, Larry A. Nagode, Charles C. Capen. (1995) Pathophysiology of Calcium Metabolism. Veterinary Clinical Pathology 24:2, 49-63
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Claudia Stiegler, Georg Leb, Reinhold Kleinert, Helga Warnkross, Sigrid Ramschak-Schwarzer, Rainer Lipp, Georg Clarici, Guenter J. Krejs, Harald Dobnig. (1995) Plasma levels of parathyroid hormone-related peptide are elevated in hyperprolactinemia and correlated to bone density status. Journal of Bone and Mineral Research 10:5, 751-759
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Kyoji Ikeda, Etsuro Ogata. (1995) Humoral hypercalcemia of malignancy: Some enigmas on the clinical features. Journal of Cellular Biochemistry 57:3, 384-391
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Hideyuki Yamato, Yumiko Nagai, Daisuke Inoue, Yasuyuki Ohnishi, Yoshito Ueyama, Hideto Ohno, Toshio Matsumoto, Etsuro Ogata, Kyoji Ikeda. (1995) In vivo evidence for progressive activation of parathyroid hormone-related peptide gene transcription with tumor growth and stimulation of osteoblastic bone formation at an early stage of humoral hypercalcemia of cancer. Journal of Bone and Mineral Research 10:1, 36-44
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Chuanyan Mao, Paul Carter, Paul Schaefer, Liyin Zhu, Justo M. Dominguez, Daniel J. Hanson, Hubert E. Appert, Kitai Kim, John M. Howard. (1995) Malignant islet cell tumor associated with hypercalcemia. Surgery 117:1, 37-40
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Mitsuko Suehiro, Minoru Murakami, Minoru Fukuchi. (1994) Circulating forms of immunoreactive parathyroid hormone-related protein for identifying patients with humoral hypercalcemia of malignancy: A comparative study with C-terminal(109–141)- and N-terminal(1–86)-region-specific PTHrP radioassay. Annals of Nuclear Medicine 8:4, 231-237
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Jan H. Graaf, Rienk Y. J. Tamminga, Willem A. Kamps. (1994) Paraneoplastic manifestations in children. European Journal of Pediatrics 153:11, 784-791
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Janet Walls, Wendy A. Ratcliffe, A. Howell, N. J. Bundred. (1994) Parathyroid hormone and parathyroid hormone-related protein in the investigation of hypercalcaemia in two hospital populations. Clinical Endocrinology 41:4, 407-413
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W. A. Ratcliffe, S. J. Bowden, F. P. Dunnet, S. Hughes, J. F. Emly, J. T. Baker, J. K. Pye, C. P. Williams. (1994) Expression and processing of parathyroid hormone-related protein in a pancreatic endocrine cell tumour associated with hypercalcaemia. Clinical Endocrinology 40:5, 679-686
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S.L. Ferrari, R. Rizzoli, J.-P. Bonjour. (1994) Effects of epidermal growth factor on parathyroid hormone-related protein production by mammary epithelial cells. Journal of Bone and Mineral Research 9:5, 639-644
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Sunil J. Wimalawansa. (1994) Significance of plasma PTH-rp in patients with hypercalcemia of malignancy treated with bisphosphonate. Cancer 73:8, 2223-2230
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A.A. Budayr, E. Zysset, A. Jenzer, D. Thiébaud, P. Ammann, R. Rizzoli, F. Jaquet-Müller, J.P. Bonjour, B. Gertz, P. Burckhardt, B.P. Halloran, R.A. Nissenson, Gordon J. Strewler. (1994) Effects of treatment of malignancy-associated hypercalcemia on serum parathyroid hormone-related protein. Journal of Bone and Mineral Research 9:4, 521-526
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John J. Wysolmerski, Arthur E. Broadus. (1994) HYPERCALCEMIA OF MALIGNANCY: The Central Role of Parathyroid Hormone-Related Protein. Annual Review of Medicine 45:1, 189-200
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M. H. Zheng, H. B. McCaughan, J. M. Papadimitriou, G. C. Nicholson, D. J. Wood. (1994) Tartrate resistant acid phosphatase activity in rat cultured osteoclasts is inhibited by a carboxyl terminal peptide (osteostatin) from parathyroid hormone-related protein. Journal of Cellular Biochemistry 54:2, 145-153
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Ljubinka A. Lozance, Katica G. Zafirovska, Stevka V Bogdanovska, Gjorgji J. Zafirovski. (1994) Primary Disseminated Form of Ewing Sarcoma in Association with Hypercalcemia and Acute Renal Failure. Renal Failure 16:4, 525-534
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Gino V. Segre, Steven R. Goldring. (1993) Receptors for secretin, calcitonin, parathyroid hormone (PTH)/PTH-related peptide, vasoactive intestinal peptide, glucagonlike peptide 1, growth hormone-releasing hormone, and glucagon belong to a newly discovered G-protein-linked receptor family. Trends in Endocrinology & Metabolism 4:10, 309-314
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Steven D. Averbuch. (1993) New bisphosphonates in the treatment of bone metastases. Cancer 72:S11, 3443-3452
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Tzu-Chen Yen, Shinn-Jang Hwang, Ching-Chen Wang, Shou-Dong Lee, Shin-Hwa Yen. (1993) Hypercalcemia and parathyroid hormone-related protein in hepatocellular carcinoma. Liver 13:6, 311-315
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C.C. Pilbeam, C.B. Alander, H.A. Simmons, L.G. Raisz. (1993) Comparison of the effects of various lengths of synthetic human parathyroid hormone-related peptide (hPTHrP) of malignancy on bone resorption and formation in organ culture. Bone 14:5, 717-720
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Anne E. de Papp, Andrew F. Stewart. (1993) Parathyroid hormone-related protein a peptide of diverse physiologic functions. Trends in Endocrinology & Metabolism 4:6, 181-187
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Kanji Sato, Yukiko Yamakawa, Kazuo Shizume, Tomoko Satoh, Kyoko Nohtomi, Hiroshi Demura, Takuhiko Akatsu, Naokazu Nagata, Tadashi Kasahara, Hiroyuki Ohkawa, Kazuoki Ohsumi. (1993) Passive immunization with anti-parathyroid hormone-related protein monoclonal antibody markedly prolongs survival time of hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors. Journal of Bone and Mineral Research 8:7, 849-860
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