Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome which is responsible for significant patient morbidity and mortality. Parathyroid hormone- related protein (PTHrP) appears to be a major hormonal mediator of HHM due to the similar biologic actions that it shares with PTH. However, despite these similar biologic actions, HHM and primary hyper- parathyroidism (HPT) have different clinical characteristics. Reasons for this are likely complex and may be partly due to other tumor- associated factors or different actions of various PTHrP fragments. The long term objectives of this proposal are to develop animal models that will define 1) the role of PTHrP and other tumor- associated factors in the pathophysiology of HHM, 2) whether other tumor- associated factors can modulate the end organ effects of PTHrP and explain differences between HHM and HPT, 3) the role of various PTHrP fragments in vivo, and 4) whether different actions of PTHrP fragments contribute to the differences between HHM and HPT. The specific research proposed is intended to accomplish the development of a system of animal models of HHM that will permit comparison of individual factors to multiple known factors in a controlled setting with standard parameters of calcium homeostasis. These models will also enable similar study of the effects of continuous tumor secretion of PTHrP alone, either intact-(1-141) or carboxyl-truncated-(1-84) or -(1-106). The research design is constructed according to the long term specific objectives. Specifically, tumor models utilizing Chinese hamster ovarian (CHO) cells transfected with the cDNA for human PTHrP-(1-141) will be characterized and compared with CHO models which secrete other hypercalcemic factors (TNF, TGF alpha and IL-6) in nude mice in a controlled setting using standard parameters of calcium homeostasis. Each respective CHO tumor will be mixed with CHO tumors expressing PTHrP-(1-141) and compared with results of each individual factor as well as with a CHO tumor that secretes human PTH-(1- 84) and a human tumor (RWGT2) that causes HHM (mediated through PTHrP). CHO tumors that secrete carboxyl-truncated PTHrP-1(84) and -(1-106) will be constructed and compared with PTHrP- (1-141) in nude mice. Parameters of calcium homeostasis to be measured in all experimental groups are whole blood ionized calcium, urinary calcium, serum phosphorus, serum 1,25 dihydroxy vitamin D as well as bone histology and histomorphometry. The role of PTHrP, PTHrP fragments and other tumor-associated factors in HHM as well as their respective contributions to the differences between HHM and HPT should be made clear through the use of these models.Ultimately, they should contribute to the development and testing of therapy for HHM.
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