Paclitaxel enhanced radiation sensitization for the suppression of human prostate cancer tumor growth via a p53 independent pathway.
BACKGROUND
This study investigated the influence of p53 status on treatment using combined paclitaxel and irradiation for human prostate cancer (PC) in vitro and in vivo.


METHODS
Enhancement of the radiation response by paclitaxel was determined by MTT and clonogenic assays in four sublines of the human PC cell line, LNCaP, stably transfected to express different p53 mutations found in PC patients. Suppression of xenograft growth by combined paclitaxel and radiation was assessed in NOD.SCID mice in vivo. Expression of p53 and downstream functional proteins, p21 and Bax, was assessed by Western blotting.


RESULTS
Paclitaxel (8-10 nM) suppressed cell proliferation by 50% by inducing G2M mitotic arrest in LNCaP cell lines transfected to overexpress wild-type or mutant p53. Exposure to 20 nM paclitaxel before radiation therapy enhanced cytotoxicity in clonogenic assays. The dose and duration of paclitaxel exposure were important in inducing both G2M arrest and cell growth suppression and were critical factors in paclitaxel/irradiation combination therapy. Western blotting indicated that combination therapy increased p21 protein expression to varying degrees in all cell lines. In vivo studies indicated that paclitaxel pre-treatment followed by irradiation significantly suppressed tumor growth compared with either treatment alone.


CONCLUSIONS
Pre-treatment with paclitaxel enhances radiation efficacy on cell killing and suppression of growth of human PC cell lines in vitro and in vivo via p53 independent pathways. Paclitaxel has potential for use as a radiosensitizer in the treatment of patients with PC with either wild-type or mutant p53 genetic status.
Zhang
An Ling
AL
Oncology Research Centre, Prince of Wales Hospital, Randwick, NSW, Australia.
Russell
Pamela J
PJ
Knittel
Tony
T
Milross
Chris
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D014964:X-Ray Therapy