ANIMAL MODELS OF HUMORAL HYPERCALCEMIA OF MALIGNANCY

Project: Research project

Description

DESCRIPTION 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.
StatusFinished
Effective start/end date4/1/933/31/99

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $75,600.00

Fingerprint

Parathyroid Hormone-Related Protein
Cricetulus
Neoplasms
Animal Models
Calcium
Nude Mice
Homeostasis
Humoral Hypercalcemia Of Malignancy
Paraneoplastic Syndromes
Transforming Growth Factor alpha
Blood Group Antigens
Parathyroid Hormone
Serum
Vitamin D
Phosphorus
Hyperparathyroidism
Interleukin-6
Research Design
Complementary DNA
Tumor Necrosis Factor-alpha

ASJC

  • Medicine(all)