Inhibition of cis-diamminedichloroplatinum (II)-induced DNA interstrand cross-link removal by 7-ethyl-10-hydroxy-camptothecin in HST-1 human squamous-carcinoma cells
✍ Scribed by Naoko Masumoto; Shuji Nakano; Taito Esaki; Hiromitsu Fujishima; Takashi Tatsumoto; Yoshiyuki Niho
- Publisher
- John Wiley and Sons
- Year
- 1995
- Tongue
- French
- Weight
- 638 KB
- Volume
- 62
- Category
- Article
- ISSN
- 0020-7136
No coin nor oath required. For personal study only.
✦ Synopsis
The combination of cis-diamminedichloroplatinum(ll) (CDDP) and 7-ethyl-I0-[4-( I -pipmidino)-I -piperidino]carbonyloxycamptothecin (CPT-I I), a topoisomerase-I inhibitor, has been shown to be synergistic in vitro and clinically active against several human cancers refractory to chemotherapy. To elucidate the mechanism of the synergistic cytotoxicity of CDDP and 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of CPT-I I, we studied the interaction of these agents using an HST-I human squamous-carcinoma cell line. Cells were exposed to the ICso concentration of SN-38 (5.0 ng/ml) for I hr and various concentrations of CDDP for I hr in several different treatment schedules. SN-38 augmented the anti-tumor activity of CDDP in all schedules, with maximal synergy observed with simultaneous administration. Evaluation of the kinetics of the removal of D N A interstrand cross-links, measured by alkaline elution, showed significant reduction of this removal in the cells exposed to SN-38 and CDDP, as compared with the cells exposed to CDDP alone. No differences, however, were found in the initially attained level of D N A interstrand cross-links induced by CDDP between these cells. Moreover, the intracellular accumulation of platinum measured by atomic-absorption spectrophotometry, was virtually identical between these cells. These results indicate that SN-38 can modulate the removal of platinum-DNA adducts. thereby potentiating the cytotoxicity of CDDP, suggesting a critical role for topoisomerase I in the repair of DNA interstrand cross-links. t 1995 H ; h -I ~t \ \ , / I N CDDP (cis-diamminedichloroplatinum(I1)) is one of the most widely used agents in combination chemotherapy for human solid tumors. The cytotoxicity of CDDP is mediated by the formation of DNA cross-links (Eastman, 1987). Although most of these lesions are intrastrand cross-links occurring between adjacent guanine nucleotides, DNA interstrand crosslinks, which constitute only about 1% of platinations, have been shown to be among the most cytotoxic of the lesions induced by CDDP (Zwelling et al., 1979). Unrepaired, the cross-links inhibit normal DNA replication and transcription, and ultimately result in cell death. Although the molecular mechanisms involved in the repair of drug-damaged DNA remain unclear, a role for topoisomcrascs, whose activities are required during DNA replication, transcription, and homologous recombination has been suggested in the repair (Crumplin, 1981). Specifically, there is evidence to suggest a role for topoisomerase I1 in the repair process (Webb et al., 1987;Cleaver, 1982;Gedik and Collins, 1990). The function of topoisomerases is to change the topological state of DNA in a 2-step process involving nicking and religating single or double strands in the phosphodiester backbone of the DNA double helix (Liu, 1989). Because DNA topoisomerase I can substitute for topoisomerase I1 in most functions, except that it can break only single strands rather than double strands, the alteration of DNA topology induced by a topoisomerase-I inhibitor can thus affect the availability of DNA sequences for platination and for subsequent repair of the CDDP-damaged DNA. However, no studies to date have demonstrated a role for topoisomerase I in the repair of CDDP-damaged DNA.
Recently, the combination of CDDP and the topoisomerase-I inhibitor CPT-11 (7-ethyl-10-[4-(1-piperidino)-l-piperi-