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

• Published in: Life sciences (1973) Vol. 68; no. 1; pp. 1 - 11
• Main Authors: Gharehbaghi, Kamran, Szekeres, Thomas, Yalowitz, Joel A., Fritzer-Szekeres, Monika, Pommier, Yves G., Jayaram, Hiremagalur N.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 24-11-2000
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antitumor activity; Cisplatin - pharmacology; Cisplatin, synergy; Cyclopentenylcytosine; Cytidine - analogs & derivatives; Cytidine - pharmacology; Drug Synergism; HT29 Cells; Human colon carcinoma HT-29; Humans; Mice; Neoplasm Transplantation; Cyclopentenylcytosine; Antitumor activity; Human colon carcinoma HT-29; Cisplatin, synergy
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/S0024-3205(00)00914-0

Cyclopentenylcytosine (CPEC) is cytotoxic to HT-29 cells
in vitro and
in vivo. Treatment with CPEC resulted in sensitizing HT-29 cells to cisplatin (CDDP), as evidenced by synergistic cytotoxicity. CPEC exhibits potent cytotoxicity to HT-29 cells
in vitro, 2 and 24 h exposure providing an LC
50 of 2.4 and 0.46 μM, respectively. Exposure of HT-29 cells to CDDP for 2 h resulted in an LC
50 of 26 μM. Treatment of HT-29 cells with 1.0 or 1.25 μM CPEC and then incubating with CDDP showed synergistic cytotoxicity. Lesser synergy 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 combined with CDDP. Synergistic antitumor activity was demonstrable
in vivo in mice transplanted with HT-29 tumor when treated with a combination of CPEC and CDDP without undue toxicity, since no excessive loss in mouse body weight or overt pathology was observed. CPEC had no influence on the total DNA adduct formation and CDDP did not affect the intracellular levels of CPEC or its metabolites, suggesting that enhanced CDDP cytotoxicity resulted from a step subsequent to excision of platinum-cross-linked DNA. These studies support a new approach for augmenting cytotoxic effect of CPEC with CDDP in treating human colon carcinoma.