Sensitizing human colon carcinoma HT-29 cells to cisplatin by cyclopentenylcytosine, in vitro and in vivo

Cyclopentenylcytosine (CPEC) is cytotoxic to HT-29 cells in vitro and in vi vo. Treatment with CPEC resulted in sensitizing HT-29 cells to cisplatin (C DDP), as evidenced by synergistic cytotoxicity. CPEC exhibits potent cytoto xicity to HT-29 cells in vitro, 2 and 24 h exposure providing an LC50 of 2. 4 and 0.46 muM, respectively. Exposure of HT-29 cells to CDDP for 2 h resul ted in an LC50 of 26 muM. Treatment of HT-29 cells with 1.0 or 1.25 muM CPE C and then incubating with CDDP showed synergistic cytotoxicity. Lesser syn ergy at very high concentrations of CPEC was demonstrated when HT-29 cells were first exposed to CDDP and then incubated with CPEC. Combination index calculations showed synergistic cytotoxicity in HT-29 cells when CPEC was c ombined with CDDP. Synergistic antitumor activity was demonstrable in vivo in mice transplanted with HT-29 tumor when treated with a combination of CP EC and CDDP without undue toxicity, since no excessive loss in mouse body w eight or overt pathology was observed. CPEC had no influence on the total D NA adduct formation and CDDP did not affect the intracellular levels of CPE C or its metabolites, suggesting that enhanced CDDP cytotoxicity resulted f rom a step subsequent to excision of platinum-cross-linked DNA. These studi es support a new approach for augmenting cytotoxic effect of CPEC with CDDP in treating human colon carcinoma. (C) 2000 Elsevier Science Inc. All righ ts reserved.