Prostate secretory protein PSP-94 decreases tumor growth and hypercalcemia of malignancy in a syngenic in vivo model of prostate cancer.
Prostate cancer is a common malignancy affecting men, which is often associated with skeletal metastases resulting in significant morbidity and mortality. In this hormone-dependent cancer, low levels of a prostate secretory protein of 94 amino acids (PSP-94) are associated with advanced disease stage. In the current study, we have examined the effect of PSP-94 on prostate cancer growth and experimental metastases to the skeleton. For these studies, MatLyLu rat prostate cancer cells were transfected with full-length cDNA encoding parathyroid hormone-related protein [PTHrP (MatLyLu-PTHrP cells)], which is known to be the major pathogenetic factor for malignancy-associated hypercalcemia. MatLyLu-PTHrP cells were inoculated s.c. into the right flank or via intracardiac route into the left ventricle of syngeneic male Copenhagen rats. Intracardiac inoculation of MatLyLu cells routinely results in the development of tumors in the lumbar vertebrae, resulting in hind-limb paralysis. Animals were infused with different doses of PSP-94 (0.1, 1.0, and 10.0 micro g/kg/day) starting on the day of tumor cell inoculation. Time of hind-limb paralysis and tumor volume were determined, and comparison was made between PSP-94-treated animals and control animals receiving vehicle alone. At the end of the study, animals were sacrificed, and plasma calcium, plasma PTHrP, and tumor PTHrP levels were determined. Whereas the highest dose of PSP-94 caused a modest but statistically significant delay in the development of hind-limb paralysis, a marked dose-dependent decrease in primary tumor volume was seen in experimental animals receiving PSP-94 due to its ability to promote tumor cell apoptosis. Furthermore, whereas control animals routinely developed hypercalcemia due to PTHrP production, treatment with PSP-94 led to a near normalization of plasma calcium and a marked reduction in PTHrP production as determined by radioimmunoassay and immunohistochemistry. Collectively, these results demonstrate the ability of PSP-94 to be an effective treatment modality for prostate cancer, where decrease in plasma PTHrP and calcium levels can serve as useful biochemical markers for monitoring the efficacy of this novel antitumor agent.
Shukeir
Nicholas
N
Department of Medicine, Physiology and Oncology, McGill University Health Centre, Montreal, Quebec, H3A 1A1 Canada.
Arakelian
Ani
A
Kadhim
Salam
S
Garde
Seema
S
Rabbani
Shafaat A
SA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary; D002118:Calcium / Q000097:blood; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones / Q000097:blood / Q000235:genetics; D011471:Prostatic Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D029584:Prostatic Secretory Proteins / Q000494:pharmacology*; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured
C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones; D029584:Prostatic Secretory Proteins; C043076:beta-microseminoprotein; D002118:Calcium