The effects of dichloromethylene diphosphonate on hypercalcemia and other parameters of the humoral hypercalcemia of malignancy in the rat leydig cell tumor |
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Authors: | Dr Raymond R Martodam Kim S Thornton Domenic A Sica Sharyn M D'Souza Lawrence Flora Gregory R Mundy |
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Institution: | (1) Procter and Gamble Company, Cincinnati, Ohio;(2) Department of Medicine, Division of Endocrinology and Metabolism, University of Texas Health Science Center, 78284 San Antonio, TX |
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Abstract: | Summary There is a high frequency of Leydig cell tumors associated with hypercalcemia in the aged Fischer 344 rat. We studied a transplantable
tumor cell line (Rice D-6) which is associated with hypercalcemia, hypercalciuria, hypophosphatemia, renal phosphate wasting,
increased urinary cyclic adenosine monophosphate (AMP) excretion, absence of bone metastases, increased osteoclastic bone
resorption, and suppressed immunoreactive parathyroid hormone (iPTH) concentrations. We examined the ability of dichloromethylene
diphosphonate (Cl2MDP) to lower serum calcium and decrease the parameters of increased bone resorption. We used this drug also as a pharmacologic
tool to determine the relationship of hypercalcemia and increased bone resorption to the abnormalities in renal tubular function
associated with the humoral hypercalcemia of malignancy.
Daily administration of Cl2MDP before development of hypercalcemia, in doses from 2.5–40 mg/kg body weight subcutaneously, delayed and suppressed both
the hypercalcemia and hypercalciuria. There was an increase in bone mass and decrease in both osteoclast number and activity
compared with bones from untreated tumor-bearing animals. The urinary hydroxyproline excretion in treated animals declined
towards the normal range. There were no significant effects on serum phosphorus, urine phosphorus, or urine cyclic AMP excretion.
These data suggest that Cl2MDP reverses the increased bone resorption that occurs in the humoral hypercalcemia of malignancy, and confirms that diphosphonates
are effective agents in the prevention and treatment of increased bone resorption associated with malignant disease. They
also suggest that renal phosphate wasting and increased urinary cyclic AMP excretion are not directly related to the hypercalcemia. |
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Keywords: | Dichloromethylene diphosphonate Hypercalcemia Rat tumor |
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