Tumor-associated Hypercalcemia Research Articles

Disruption of a Nuclear NFATc2 Protein Stabilization Loop Confers Breast and Pancreatic Cancer Growth Suppression by Zoledronic Acid

The aminobisphosphonate zoledronic acid has elicited significant attention due to its remarkable anti-tumoral activity, although its detailed mechanism of action remains unclear. Here, we demonstrate the existence of a nuclear GSK-3β-NFATc2 stabilization pathway that promotes breast and pancreatic cancer growth in vitro and in vivo and serves as a bona fide target of zoledronic acid. Specifically, the serine/threonine kinase GSK-3β stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2-mediated proteolysis. Zoledronic acid disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK-3β inhibition and induction of HDM2 activity. Upon nuclear accumulation, HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues Lys-684/Lys-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis-induced constitutive serine phosphorylation (Ser-215, Ser-219, and Ser-223) of the SP2 domain prevents NFATc2 from HDM2-mediated ubiquitination and degradation and consequently rescues cancer cells from growth suppression by zoledronic acid. In conclusion, this study demonstrates a critical role of the GSK-3β-HDM2 signaling loop in the regulation of NFATc2 protein stability and growth promotion and suggests that double targeting of this pathway is responsible, at least to a significant part, for the potent and reliable anti-tumoral effects of zoledronic acid.

A novel third generation bisphosphonate, minodronate (YM529), prevented proliferation and migration of hepatocellular carcinoma cells through inhibition of mevalonate pathway

Skeletal metastases and bone metasitasis are a common occurrence in patients with advanced hepatocellular carcinoma (HCC). Bisphosphonates (BPs), which are used for the treatment of osteoporosis and tumor-associated hypercalcemia, have recently been reported to decrease skeletal morbidity in patients with metastatic bone disease. Several studies revealed that nitrogen-containing BPs (N-BPs) could inhibit tumor growth and migration, indicating the possibility that N-BPs have direct inhibitory effects. We aimed to determine the effects of novel a N-BP (YM529) on human HCC cells in vitro. HCC cells were treated with various concentrations of YM529 and the growth inhibition rate was determined. Apoptosis was evaluated by caspase-3/7 assay and caspase-9 cleavage detection. The effects of YM529 on the migration of HCC cells induced by hepatocyte growth factor (HGF) were determined by cell migration assay. To evaluate the involvement of the mevalonate pathway, farnesol (FOH) and geranylgeraniol (GGOH) were added. YM529 inhibited the proliferation of HCC cells in a dose-dependent manner. The activation of caspase-3/7 and cleavage of caspase-9 demonstrated the involvement of apoptosis in cytotoxicity. GGOH reduced the growth inhibitory effect of YM529 and suppressed the induction of caspase-3/7 activities by YM529 on HCC cells. YM529 inhibited tumor cell migration induced by HGF and this effect was reduced by co-treatment with GGOH. YM529 inhibited the cell proliferation and migration of HCC cells, implicating the involvement of the mevalonate pathway. These results suggest that N-BPs are potential agents for the treatment of HCC skeletal metastases.

Tumor-Associated Hypercalcemia in a Patient with Paget's Disease

Paget's disease of the bone, which is characterized by a focal region of highly exaggerated bone remodeling, is very rare in Asia. Most patients with Paget's disease are asymptomatic; they are normocalcemic and show elevated alkaline phosphatase levels. Hypercalcemia in patients with Paget's disease has rarely been reported. We report one Chinese patient with Paget's disease involving the maxilla bone with an initial presentation of facial cellulitis. Asymptomatic hypercalcemia with a low-normal intact parathyroid hormone level developed 9 years later. After clodronate treatment, the level of alkaline phosphatase normalized, but the hypercalcemia did not respond adequately. After analysis of tumor markers and imaging studies, a clinical diagnosis of pancreatic adenocarcinoma with multiple hepatic and lung metastases with pleural effusion was made. We suggest that malignancy-associated hypercalcemia should be considered as one of the causes of hypercalcemia in patients with Paget's disease.

Phase I and pharmacokinetic study of the oral tris-(8-quinolinolato)gallium(III) complex (FFC11, KP46) in patients with solid tumors - a study of the CESAR Central European Society for Anticancer Drug Research - EWIV

3205 Background: FFC11 is an orally bioavailable gallium complex, which exerts its antitumoral activity via inhibition of ribonucleotide reductase, induction of S phase arrest and apoptosis. In preclinical models FFC11 proved to be a stronger anticancer agent than gallium nitrate and it was effective against a model of tumor-associated hypercalcemia. Methods: FFC 11 is administered orally for 14 days followed by a 14-days recovery period representing one cycle of therapy. The phase I trial is started at 30 mg/m2. Dose escalation (DE) is performed acc. to an accelerated dose titration design with escalation steps of 100%. The accelerated phase is finished when 1 pt exhibits dose limiting toxicity (DLT) or 2 pts experience toxicities ≥ grade (G) 2 NCI-CTC. Further DE will be done acc. to a modified Fibonacci scheme. Tumor response is assessed using the RECIST criteria. PK parameters were estimated assuming a one compartment model. Results: 7 pts were entered at the following dose levels (DL): 30 mg/m2, 60 mg/m2, 120 mg/m2, 240 mg/m2 and 480 mg/m2. Patient’s profile comprised the following tumor entities: parotid gland, stomach, renal cell (4) and ovarian cancer. Most pts were heavily pretreated. The adverse events for which a relationship to the study medication could not definitely be ruled out were neutropenia (G2 at DL1) (1pt) and anemia (G2 at DL1) (2pts), stomatitis and conjunctivitis (G1 at DL2) (1pt), dizziness, headache and acne (G1 at DL4) (1pt), fatigue (G1) and diarrhoea (G3) both at DL5 (1pt); the latter represented a DLT. Further enrolment on this DL was terminated due to feasibility reasons. In one out of the 4 pts with renal cell carcinoma (RCC) an unconfirmed partial response (PR) has been observed after 8 weeks and in a second pt with RCC the disease was stabilized for 29 weeks. Peak plasma levels were reached 5–7 h after intake. PK analysis revealed a long terminal half-life (28 h), a high CL/F (42 L/h) and a large V/F (1700 L). Conclusions: FFC11 has been well tolerated with some preliminary evidence of efficacy in RCC. FFC11 will be developed further after the production of higher dosed tablets. Supported by Faustus Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Faustus Cie

Current Management Strategies for Hypercalcemia

The two most common causes of hypercalcemia are primary hyperparathyroidism and neoplastic disease. Parathyroidectomy is the only curative intervention for the former condition. In the rare cases of patients with primary hyperparathyroidism who present with clinical symptoms due to their hypercalcemia, pharmacological treatment may be required. Fluid repletion and intravenous (IV) administration of bisphosphonates are recommended in the literature. Calcium receptor agonists (calcimimetic agents) are at the present time only available for use within clinical trials. Cancer patients usually present with symptoms of hypercalcemia. Rapid institution of antihypercalcemic treatment is essential in preventing life-threatening deterioration. Fluid repletion and administration of bisphosphonates are the treatment mainstays in hypercalcemia of malignancy. Five bisphosphonates are currently licensed in Europe for treatment of tumor-associated hypercalcemia: etidronate, clodronate, pamidronate, ibandronate, and zoledronate. In the US, pamidronate and zoledronate are licensed for use in this indication. Bisphosphonates containing nitrogen atoms (e.g. pamidronate, ibandronate, and zoledronate) are more potent than those without (e.g. etidronate, clodronate, and tiludronate). In patients with malignant hypercalcemia, the efficacy of the individual bisphosphonate depends on dose administered and initial serum calcium concentration. At present, pamidronate has been studied in the greatest number of investigations and in the largest number of patients. In the literature, the efficacy of pamidronate in restoring normocalcemia ranges between 40% and 100%, depending on the dose used and baseline serum calcium concentration. More recently, one study reported that pamidronate was inferior to zoledronate. In this study, the duration of response was also longer in the two zoledronate groups (30 and 40 days) than in the pamidronate group (17 days). The most serious adverse events of bisphosphonates concern renal function. Increases in serum creatinine levels have been more frequently reported following treatment of tumor-associated hypercalcemia with etidronate (8%) and clodronate (5%) than with the nitrogen-containing bisphosphonates pamidronate (2%) and ibandronate (1%). The frequency of increases in serum creatinine levels following treatment with zoledronate is difficult to estimate. Administration of the nitrogen-containing bisphosphonates has been associated with transient (usually mild) fever, lymphocytopenia, malaise, and myalgias. These events occur within 36 hours of the first dose and are self-limiting. Hypocalcemia occurs in up to 50% of patients treated with bisphosphonates for hypercalcemia of malignancy, although symptomatic hypocalcemia is rare. The toxicity and low efficacy of plicamycin (mithramycin) mean that use of this agent should be restricted to patients with hypercalcemia of malignancy who fail to respond to IV bisphosphonates. Calcitonin is characterized by good tolerability but poor efficacy in normalizing the serum calcium level. However, a major advantage of calcitonin is the acute onset of the hypocalcemic effect, which contrasts with the delayed but more pronounced effect of bisphosphonates. Combination calcitonin and bisphosphonate treatment may therefore be of value when rapid reduction of serum calcium is warranted. Gallium nitrate may be a valuable treatment for hypercalcemia of malignancy. It is characterized by high efficacy and few adverse events apart from renal toxicity (10% of cases). However, data are very limited and further trials are necessary.

Efficacy of YM-175, a new bisphosphonate, in the treatment of metastatic bone tumor from breast cancer and its effect on scintigraphy

Background Bisphosphonates are powerful inhibitors of osteoclast-mediated bone resorption. They are effective in the treatment of Paget's disease of the bone, tumor-associated hypercalcemia, and osteoporosis. They are also used to treat metastatic bone disease. YM-175 is a new highly potent bisphosphonate. Bisphosphonates are also used as radiopharmaceuticals in bone scintigraphy. The data remain unclear as to whether or not the administration of large amounts of bisphosphonate interferes with the bone scintigraphy process.

Pamidronate treatment in patients with tumor-associated hypercalcemia: pharmacological effects and pharmacokinetics.

The purpose of this study was to investigate the effects of pamidronate, a second generation bisphosphonate, on the change in calcium homeostasis in patients with tumor-associated hypercalcemia. Eight patients with tumor-associated hypercalcemia received intravenous infusion of pamidronate (45 mg) and their high mean serum calcium concentration significantly decreased from 3.56 mmol/L to 2.62 mmol/L7 days after treatment. Serum intact PTH before treatment had been suppressed to below normal in all patients but returned to normal range in six patients within 7 days after treatment. Urinary PTH related peptide (PTHrP) excretion before treatment had been elevated in seven patients and then significantly increased further after pamidronate therapy. The serum bone Gla protein concentration was not apparently changed by the treatment. Pamidronate in serum was rapidly eliminated after the treatment and urinary excretion reached a plateau on the second day (13.8% of the administered dose), suggesting that the major portion of the infused dose had been distributed to the bone and other tissues. These findings suggest that pamidronate has a potent hypocalcemic effect and that PTHrP production in malignant tumors could be affected by pamidronate therapy.

Urinary pyridinium cross-links as markers of bone resorption in tumor-associated hypercalcemia.

Osteoclastic activity is increased in tumor-associated hypercalcemia, which, thus, constitutes an excellent opportunity to assess new markers of the bone resorption rate. We have measured the fasting urinary excretion of the pyridinium cross-links pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) in 36 hypercalcemic cancer patients (mean +/- SD, 3.2 +/- 0.4 mmol/L for total serum Ca and 1.66 +/- 0.24 mmol/L for Ca2+). Thirty-two of them were reevaluated after treatment with iv bisphosphonates. Urinary Pyr and D-Pyr levels were higher than those in healthy controls (130 +/- 62 vs. 40 +/- 19 nmol/mmol creatinine for Pyr and 20 +/- 15 vs. 6 +/- 3 nmol/mmol creatinine for D-Pyr; P less than 0.001 for both). This represented a mean 3.3-fold increase over the normal mean compared to 5.8- and 3.4-fold increases for fasting urinary Ca and hydroxyproline, respectively. Individual values were elevated in 83% and 75% of the cases for Pyr and D-Pyr compared to 97% and 83% for urinary Ca and hydroxyproline, respectively. The levels of Pyr and D-Pyr tended to be higher in patients with head and neck tumors than in patients with breast cancer. Urinary Pyr and D-Pyr correlated with each other (r = 0.72; P less than 0.001) and were highly correlated with hydroxyproline (r = 0.68 and 0.83, respectively; P less than 0.001 for both), but poorly correlated with urinary Ca (r = 0.21; P = NS and r = 0.42; P = 0.01, respectively), suggesting that these markers reflect different events of bone resorption. Similarly, after bisphosphonate therapy, urinary Pyr and D-Pyr levels fell by 31% and 50%, respectively, compared to 38% for hydroxyproline and 76% for urinary Ca. There was a significant correlation between posttreatment D-Pyr and serum Ca levels (r = 0.43; P less than 0.05). In summary, we found that the urinary excretion of Pyr and D-Pyr was markedly increased in hypercalcemic cancer patients and was adequately lowered by bisphosphonate therapy. The urinary excretion of the pyridinium cross-links, especially D-Pyr, should be helpful to specifically quantitate bone matrix resorption and monitor the inhibition of bone resorption in cancer patients receiving antiosteolytic drugs.

Modified Immunoradiometric Assay of Parathyroid Hormone-Related Protein: Clinical Application in the Differential Diagnosis of Hypercalcemia

We have developed a sensitive, specific solid-phase immunoradiometric assay (IRMA) of parathyroid hormone-related protein (PTH-RP) with use of affinity-purified polyclonal immunoglobulins. Antibodies recognizing PTH-RP(37-74) are immobilized to a polystyrene bead to "capture" analytes from the sample; antibodies to epitopes within the 1-36 amino acid region of PTH-RP are labeled with 125I. This IRMA recognizes PTH-RP(1-74) and PTH-RP(1-86) equivalently, but does not detect N-terminal or C-terminal fragments of PTH-RP, intact human parathyrin (PTH), or fragments of PTH. PTH-RP is not stable in plasma at 3-5 degrees C or room temperature, but a mixture of aprotinin (500 kallikrein units/L) and leupeptin (2.5 mg/L) improves PTH-RP stability in blood samples. In plasma collected in the presence of these protease inhibitors from normal volunteers and patients with various disorders of calcium metabolism, PTH-RP concentrations were above normal (greater than 1.5 pmol/L) in 91% (42 of 46) of patients with hypercalcemia associated with nonhematological malignancy. In plasma from patients with other hypercalcemic conditions (e.g., primary hyperparathyroidism, sarcoidosis, and vitamin D excess), PTH-RP was undetectable. Above-normal concentrations of PTH-RP and total calcium decreased to normal in a patient with an ovarian cyst adenocarcinoma after surgical removal of the tumor. We conclude that PTH-RP is related to and probably the causative agent of hypercalcemia in most patients with cancer, and that measurements of PTH-RP are useful in the diagnosis and management of patients with tumor-associated hypercalcemia.

Efficacy and safety of the bisphosphonate tiludronate for the treatment of tumor-associated hypercalcemia

Tiludronate is a new bisphosphonate whose efficacy has already been reported for the prevention of postmenopausal bone loss. We have evaluated its efficacy and tolerance by a dose-finding study in 19 hypercalcemic cancer patients after adequate intravenous (iv) rehydration. Treatment consisted of 3 days of iv tiludronate given at doses of 3.0 mg/kg/day ( n = 3), 4.5 mg/kg/day ( n = 3), or 6.0 mg/kg/day ( n = 13); this iv therapy was followed by 17 days of oral tiludronate, 400 mg ( n = 13) or 800 mg ( n = 6) daily. Treatment had to be discontinued in 9 patients, including 3 because of evident treatment failure and 1 because of severe toxicity. After iv tiludronate, 13/18 patients had a normal Ca level, including 10/12 who had received 6.0 mg/kg/day, but Ca 2+ levels were fully normalized in only 4/18 and 3/12 patients, respectively. After 6.0 mg/kg/day, Ca levels had fallen from 12.1 ± 0.3 to 10.0 ± 0.4 mg/dl ( P < 0.0005), whereas fasting urinary calcium excretion went from 0.639 ± 0.099 to 0.272 ± 0.054 mg Ca/mg creatinine on d4 ( P < 0.001). On the other hand, oral tiludronate was unable to normalize Ca in patients who were still hypercalcemic after the iv course, although the daily administration of 800 mg appeared to be more efficient than the 400 mg daily dosage. The administration of tiludronate caused an increase in serum phosphate levels, from 2.9 ± 0.2 to 3.7 ± 0.2 mg/dl after the iv course, probably through an increase in the TmP/GFR index, which went from 2.3 ± 0.2 to 3.6 ± 0.4 mg/dl ( P < 0.05). Three patients had an increase in serum creatinine levels after the iv course, one obese patient developing an acute renal insufficiency; during oral tiludronate therapy, 5 other patients also presented an increase in serum creatinine levels. Oral tiludronate administration was also associated with occasional nausea and vomiting. In summary, compared with aminobisphosphonates, tiludronate is not indicated for the treatment of tumor-associated hypercalcemia because of the need tor high iv doses which are potentially nephrotoxic.

The synthetic human parathyroid hormone-related protein is inhibited by a parathyroid hormone antagonist in rats in vivo

The structure of a novel protein, parathyroid hormone-related protein (PTHrP), secreted by human tumors associated with hypercalcemia has recently been determined. Administration of a synthetic fragment of this protein in vivo reproduces features of the clinical paraneoplastic syndrome of humoral hypercalcemia of malignancy and produces biologic responses closely similar to those obtained with parathyroid hormone (PTH). A PTH antagonist designed to reversibly occupy PTH receptors inhibited major actions of the tumor peptide in vivo, including phosphaturia, urinary cAMP excretion, and increased serum ionized calcium. These studies indicate that PTHrP and PTH mediate their bioactivities through shared receptors in vivo and establish a potential specific mechanism-based approach utilizing PTH antagonists for the therapy of tumor-associated hypercalcemia.

Conditioned medium from ras oncogene-transformed nih 3T3 cells induces bone resorption in vitro

Tumor-associated hypercalcemia is due, in part, to enhanced osteoclastic bone resorption induced by soluble factors elaborated from malignant cells. ras transformation of NIH 3T3 cells results in a 50-fold induction of cathepsin L mRNA and secretion of the corresponding protein. Since cathepsin L is an acid proteinase we asked whether conditioned medium from these cells would directly increase calcium release from bone in vitro. We tested conditioned medium obtained after 72 h culture of NIH 3T3 ras-transformed cells (DT) or nontransformed NIH 3T3 cells (3T3) and identical medium not exposed to cells (Ctl). Incubation of either live or dead neonatal mouse calvaria for 48 h in DT-conditioned medium increased calcium release compared to bones incubated with 3T3 medium. In both states the increased calcium release with DT medium was blocked by 0.25 mM E-64, a general cysteine proteinase inhibitor, and 1 microM Z-Phe-Ala-CH2F, a specific inhibitor of cathepsin L activity. Thus, conditioned medium from ras-transformed cells enhances calcium release in both live and dead bone. Since cathepsin L is the major protein secreted by these cells and the effect of DT-conditioned medium is blocked by a specific inhibitor of cathepsin L, these studies suggest that this acid proteinase acts directly on bone mineral to enhance net calcium release.

A tumor-secreted protein associated with human hypercalcemia of malignancy. Biology and molecular biology.

This investigation addresses a theoretical concept of tumor pathogenesis proposed over 40 years ago, namely that malignancy-associated hypercalcemia can result from endocrine secretion by tumors of a PTH-like factor. These studies demonstrate that a fragment of hHCF alone, without added or tumor-secreted cofactors or hormones, can produce hypercalcemia and other biochemical abnormalities associated with HHM. The hypercalcemia can be generated by hHCF-(1-34)NH2 action on bone, although kidney and gut could contribute to the HHM syndrome when it occurs naturally. No other tumor-secreted peptide displays this biological profile. These studies establish one (PTH-like) mechanism by which human tumors could produce hypercalcemia. Furthermore, the finding that hHCF-(1-34)NH2 is more potent than PTH in some systems is of considerable interest for the future design of hormone analogs. A broad spectrum of biological properties of hHCF-(1-34)NH2, including production of components of the HHM syndrome, can be inhibited by a PTH antagonist. Because [Tyr-34]bPTH-(7-34)NH2 selectively and competitively occupies PTH receptors, our studies demonstrate formally that hHCF-(1-34)NH2 mediates some (and perhaps all) of its actions via receptors conventionally regarded as intended for interaction with PTH, but which actually may be present to allow for expression of bioactivity of both secreted proteins. Although some structural homology is shared by the two hormones and many contribute to interaction with receptors, the disparity in structure, especially within the 1-34 domains responsible for bioactivity in both hormones, is more pronounced. The similarity in biological profiles despite structural differences between hHCF and PTH is emphasized by the inhibitory action of [Tyr-34]bPTH-(7-34)NH2 against the tumor peptide even in the absence of much of the homologous region in the PTH antagonist. This investigation provides impetus for designing more potent antagonists, which must now be regarded more appropriately as inhibitors of both PTH and hHCF. Such antagonists may best be generated from hybrid structures of the two hormones. In any case, these studies establish a promising new approach to therapy of tumor-associated hypercalcemia.

Dose/response study of aminohydroxypropylidene bisphosphonate in tumor-associated hypercalcemia

Bisphosphonates (or diphosphonates) constitute a major advance in the treatment of tumor-associated hypercalcemia and also have the potential to prevent or reverse osteolysis in normocalcemic patients. Available information on adequate therapeutic doses and potential toxicity is, however, very fragmentary. This report describes a phase I study of one of the most promising bisphosphonates currently available, aminohydroxypropylidene bisphosphonate (AHPrBP or APD), in tumor-associated hypercalcemia. Only patients remaining hypercalcemic after 48 hours of rehydration were evaluated, and antineoplastic therapy was delayed at least until a normal serum calcium level was reached. AHPrBP was given as two-hour daily infusions for three days, and three different patients were treated at each of the six following dosage levels: 0.01, 0.05, 0.25, 0.75, 1.5, and 3.0 mg/kg per day. The two lowest dosages levels were insufficient to normalize serum and urinary calcium levels, but the efficacy of the four other dosages was very similar. Plasma immunoreactive parathyroid hormone levels increased as a function of calcium levels, whereas urinary hydroxyproline levels did not prove to be a very useful measure of AHPrBP's effects on bone resorption. The drug was generally very well tolerated: only six patients had transient fever and/or decreases in lymphocyte count that were not clearly related to AHPrBP dosage. The only real problem was observed at the highest dosage of 3.0 mg/kg per day in an obese woman in whom high fever and hypotension developed. Efficacy and tolerance in dehydrated patients were verified by treating seven other patients, not previously rehydrated, at 1.0 mg/kg per day for three days. In summary, the therapeutic range of AHPrBP, given for three days as a two-hour infusion daily, lies between 0.25 and 1.5 mg/kg per day. Fasting urinary calcium levels are probably the most reliable and easily measured parameter to monitor AHPrBP's inhibition of bone resorption in normocalcemic patients.

Serum osteocalcin (BGP) in tumor-associated hypercalcemia.

Serum osteocalcin (BGP) is a new marker of bone turnover that reportedly evaluates bone formation. Thus, its measurement could assess the bone formation rate in tumor-associated hypercalcemia. We measured concentrations of BGP and other parameters of bone metabolism in 54 untreated hypercalcemic cancer patients as compared to 109 healthy subjects. Primary tumor sites were breast (19), lung (11), head and neck (6), multiple myeloma (3), kidney (2), and various (11) or multiple (2). Mean BGP levels were higher in the hypercalcemic subjects, 4.6 +/- 0.4 (SEM) ng/ml, than in the normal subjects, 3.6 +/- 0.1 ng/ml (p less than .05), and were normalized in the 22 patients who could be reevaluated after successful treatment of hypercalcemia with intravenous aminohydroxypropylidene diphosphonate (APD). There was no correlation of BGP levels with age, sex, or renal function. Compared with the Gaussian distribution in the normal subjects, there was a considerable scatter of the data in hypercalcemic patients, suggesting the existence of defined subgroups with abnormally low or abnormally high values. However, we found no significant relationship of BGP concentrations with tumor site or histology or with bone metastatic involvement. We found also no significant correlation between concentrations of serum BGP and total or ionized calcium, alkaline phosphatase, parameters of bone resorption, and indices of parathyroid function. In summary, serum BGP levels were slightly elevated in tumor-associated hypercalcemia and were normalized after successful treatment of hypercalcemia. More importantly, BGP concentrations varied widely even in the subgroups of patients with hypercalcemia accompanying massive bone metastatic involvement or in the patients without detectable skeletal metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypercalcemia, excessive bone resorption, and neutrophilia in mice bearing a mammary carcinoma.

In an attempt to gain insight into the relationship between bone marrow and bone tissue, studies of bone metabolism and quantitative analysis of bone structure were carried out in mice following a transplantation of a granulocytosis-inducing mammary carcinoma. With the progression of the tumor growth and development of granulocytosis, there was a sharp increase in plasma calcium and urine calcium, both reaching over 200% of control values. Hypercalcemia was associated with a significant increase in urinary hydroxyproline (P less than 0.005), an increase in marrow medullary area (P less than 0.05), and an increase in number of endosteal osteoclasts (P less than 0.005), together indicating that the cause of hypercalcemia was an increase in bone resorption. In parallel with hypercalcemia and hypercalcuria, there was an increase in urinary cyclic AMP excretion. The removal of the tumor normalized both blood neutrophil counts and plasma calcium levels, suggesting that a humoral agent from the tumor tissue, rather than tumor metastasis to bones, may be responsible for the phenomena. These studies documented the association of excessive bone resorption in this animal model of tumor-induced neutrophilia; the model may prove useful for studies of tumor-associated hypercalcemia as well as studies of marrow and bone interactions.

Hypercalcemia associated with renal cell carcinoma: Probable role of neoplastic stromal cells

Sarcomatous proliferation of the fibroblast-like stromal cells in renal cell carcinoma was found in three patients who had apparently tumor-associated hypercalcemia but no evidence of bone metastases. The proliferation of stromal cells was not found in 20 patients who also had renal cell carcinoma without hypercalcemia. Immunoreactive parathormone-like substance was detected in two of the three patients with hypercalcemia, despite high levels of serum calcium. The parathormone assay was not conducted on the third hypercalcemic patient, however. Buffer extract from one of the tumors associated with hypercalcemia was able to elicit an increase of the serum calcium in rats, whereas buffer extract from a tumor not associated with hypercalcemia failed to induce hypercalcemia in rats. Findings suggest that the stromal cells of renal cell carcinoma may play a role in the tumor-associated hypercalcemia. The exact nature of the hypercalcemic agent is uncertain. However, in the case studied it appears that a parathormone-like substance was responsible.