Telomerase enzyme inhibition (TEI) and cytolytic therapy in the management of androgen independent osseous metastatic prostate cancer.
BACKGROUND
Recurrent prostate cancer can be osseous, androgen independent and lethal. The purpose is to discern the efficacy of synthetic small molecule telomerase enzyme inhibitors (TEI) alone or in combination with other cytotoxic therapies in controlling metastatic osseous prostate cancer.


METHODS
C4-2B was pre-treated with a match or mismatch TEI for 6 weeks and then inoculated into nude mice subcutaneously or intraosseously. In a separate experiment, untreated C4-2B was injected into femur of nude mice. The mice were divided into seven systemic "combination" treatment groups of control, Ad-BSP-E1a virus, docetaxel, mismatch and match TEI. Serum PSA was followed longitudinally. Histology analyses and histomorphometry were performed. Repeated measure analysis was applied for statistical analysis and Bonferroni method was used in multiple comparisons.


RESULTS
In the pre-treated study, the PSA of match treated cells in subcutaneous or intraosseous model was significantly lower than mismatch TEI or PBS treated group (P < 0.05). Histology revealed increased fibrosis, apoptosis and decreased PSA staining in the match TEI treated subcutaneous xenografts. In the combination treatment study, the PSA was significantly lower in single/double treatment and triple treatment than control (P < 0.05). Histology revealed that triple therapy mice had normal femur architecture. Histomorphometrics revealed that the area of femur tumor and woven bone was significantly positively correlated (P = 0.007).


CONCLUSIONS
Multiple lines of data point toward the efficacy of systemically administered telomerase inhibitors. Combining cytotoxic regimens with telomerase inhibitors could be beneficial in controlling prostate cancer. Clinical trials are warranted to explore the efficacy of TEI in prostate cancer.
Li
Yingming
Y
Department of Urologic Surgery, Center for Prostate Cancer, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Malaeb
Bahaa S
BS
Li
Zhong-Ze
ZZ
Thompson
Melissa G
MG
Chen
Zhi
Z
Corey
David R
DR
Hsieh
Jer-Tsong
JT
Shay
Jerry W
JW
Koeneman
Kenneth S
KS
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020320:Oligoribonucleotides, Antisense / Q000627:therapeutic use; D017430:Prostate-Specific Antigen / Q000097:blood / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D043823:Taxoids / Q000627:therapeutic use*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020320:Oligoribonucleotides, Antisense; D043823:Taxoids; D000077143:Docetaxel; D019098:Telomerase; D017430:Prostate-Specific Antigen