Increased sensitivity of a metastatic model of prostate cancer to a novel tetravalent platinum analog.
BACKGROUND
DACH-Ac-Pt [(1R,2R-diaminocyclohexane)-(trans-diacetato)-(dichloro)-platinum(IV)] is a novel cisplatin (CDDP) analog, and we have evaluated its potential activity in human prostate cancers.


METHODS
Cytotoxic, biochemical pharmacologic, cell cycle, and Western blot evaluations were conducted with platinum agents to assess the role of p53 genotype and androgen-dependence status on cellular response.


RESULTS
CDDP and DACH-Ac-Pt were equiactive against mutant p53 and androgen-independent DU-145 or PC-3 tumor cells. In wild-type p53 cells, CDDP was threefold more potent against androgen-dependent LNCaP than isogenic androgen-independent LNCaP-LN3 cells. However, the analog was equipotent in these two wild-type p53 tumor models. The greater potency of DACH-Ac-Pt than CDDP in wild-type p53 cells was not due to increased cellular drug uptake or increased adduct levels, but correlated with a lower tolerance to DNA damage. The analog also activated the p53-p21(WAF1/CIP1) signal transduction pathway more efficiently in LNCaP and LNCaP-LN3 cells, and this induced G(1)-phase cell-cycle arrest. CDDP, in contrast, activated this pathway efficiently in LNCaP cells only. In addition, and compared to CDDP, DACH-Ac-Pt was more effective in inducing Bax and increasing the Bax/Bcl-2 ratios in both the tumor models.


CONCLUSIONS
DACH-Ac-Pt is highly effective against wild-type p53 LNCaP and its LN3 variant, and this activity is androgen-independent. The differential induction of p21(WAF1/CIP1) and increase in Bax/Bcl-2 ratios with CDDP and DACH-Ac-Pt in LNCaP-LN3 cells appear to be linked to the relative activity of the two agents against this model.
Mujoo
Kalpana
K
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Watanabe
Masayuki
M
Khokhar
Abdul R
AR
Siddik
Zahid H
ZH
D000728:Androgens / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019938:Cyclin D1 / Q000187:drug effects; D018736:DNA Adducts / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein
C119451:(diaminocyclohexane)(diacetato)(dichloro)platinum; D000728:Androgens; D000970:Antineoplastic Agents; C494826:BAX protein, human; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019938:Cyclin D1; D002945:Cisplatin