A synthetic 15-mer peptide (PCK3145) derived from prostate secretory protein can reduce tumor growth, experimental skeletal metastases, and malignancy-associated hypercalcemia.
In previous studies, we have shown that prostate secretory protein (PSP-94) can reduce prostate cancer growth in vivo. In the current study, we identified the amino acid sequence of PSP-94 that is required for eliciting this response. For these studies, we used rat prostate cancer Mat Ly Lu cells overexpressing parathyroid hormone-related protein (PTHrP), which is the main pathogenetic factor responsible for hypercalcemia of malignancy. Synthetic peptides corresponding to amino acids 7-21 (PCK721), 31-45 (PCK3145), and 76-94 (PCK7694) of PSP-94 were synthesized. Only PCK3145 showed a significant reduction in tumor cell proliferation. For in vivo studies, syngenic male Copenhagen rats were inoculated s.c. with Mat Ly Lu cells overexpressing PTHrP into the right flank or into the left ventricle via intracardiac injection, which results in experimental metastases to the lumbar vertebrae causing hind-limb paralysis. Animals were infused with different doses (1, 10, and 100 microg/kg/day) of peptides for 15 days, and the effect of these treatments on tumor volume, skeletal metastases, or development of hind-limb paralysis was determined. Treatment with PCK3145 resulted in a dose-dependent decrease in tumor volume and delay in the development of skeletal metastases. Bone histomorphometry showed that after intracardiac inoculation of tumor cells, the highest dose of PCK3145 (100 microg/kg/day) resulted in reducing skeletal tumor burden, which delayed the development of hind-limb paralysis. Treatment with PCK3145 led to reduction of plasma calcium and PTHrP levels and a significant decrease in PTHrP levels in the primary tumors and in vertebrae of experimental animals. These effects of PCK3145 were due to its ability to promote tumor cell apoptosis. Collectively, the results of these studies have demonstrated the ability of a small peptide derived from PSP-94 to reduce tumor volume and experimental skeletal metastases-results that will be highly beneficial in the continued development of this peptide as a novel therapeutic agent for patients with hormone refractory, late-stage prostate cancer.
Department of Medicine, Physiology, and Oncology, McGill University Health Centre, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada.
Nicholas
N
Shukeir
Ani
A
Arakelian
Gaoping
G
Chen
Seema
S
Garde
Marcia
M
Ruiz
Chandra
C
Panchal
Shafaat A
SA
Rabbani
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D006614:Hindlimb / Q000473:pathology*; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D010446:Peptide Fragments / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D029584:Prostatic Secretory Proteins / Q000627:therapeutic use*; D051381:Rats; D014407:Tumor Cells, Cultured
D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D029584:Prostatic Secretory Proteins; C043076:beta-microseminoprotein; D002118:Calcium