Combined low-dose imatinib mesylate and paclitaxel lack synergy in an experimental model of extra-osseous hormone-refractory prostate cancer.
OBJECTIVE
To determine the efficacy of low-dose imatinib mesylate (STI571) alone or combined with a taxane (paclitaxel) in inhibiting the growth of experimental extra-osseous hormone-refractory prostate cancer.


METHODS
Orthotopic PC3 prostate tumours were established in male severe combined-immunodeficient mice; on day 3 the mice were randomly assigned to one of four groups: paclitaxel 10 mg/kg intraperitoneally once a week; STI571 50 mg/kg once a day for 6/7 weekdays; combined paclitaxel and STI571; and vehicle-treated controls. On day 40, the primary prostate tumour and metastatic lymphadenopathy were removed and measured. Effects were correlated with tumour cell proliferation and microvessel density.


RESULTS
Paclitaxel reduced the mean tumour weight and volume by 21.3% (not significant) and 73.7% (P < 0.05), respectively, compared to controls, and reduced the number of lymph node metastases by 49.1% (P < 0.05) and mean lymph node size by 13.5% (not significant). Adding low-dose STI571 had a small additive effect on tumour weight and the incidence of lymph node metastases, but this was not significant compared to paclitaxel alone. STI571 alone did not inhibit tumour progression. Antitumour effects were associated with parallel changes in tumour cell proliferation with no significant changes in neo-angiogenesis.


CONCLUSIONS
Combined low-dose STI571 and paclitaxel had little synergy in this experimental model. Low-dose STI571 monotherapy was not effective in extra-osseous disease, apparently due to a site-specific failure to up-regulate beta-platelet-derived growth factor receptor expression in prostate cancer cells and associated tumour stroma.
Corcoran
Niall M
NM
Department of Urology, Royal Melbourne Hospital, Parkville, Melbourne, Australia. Neil.Corcoran@mh.org.au
Costello
Anthony J
AJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000032:analysis; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D000068877:Imatinib Mesylate; D008297:Male; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D010879:Piperazines / Q000008:administration & dosage* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000627:therapeutic use; D011897:Random Allocation; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis; D017211:Treatment Failure
D001549:Benzamides; D014408:Biomarkers, Tumor; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D017239:Paclitaxel