Enhancement of camptothecin-induced cytotoxicity with UCN-01 in breast cancer cells: abrogation of S/G 2 arrest

Abstract

We have shown previously that the cytotoxicity of CPT is correlated with cell cycle response in normal and tumor cells. Low doses of CPT arrest cells in the G(2)/M phase and inhibit DNA synthesis, but higher doses cause arrest of cells in S phase. Thus modulation of events at the S and G(2) checkpoints may provide an opportunity to enhance CPT-induced cytotoxicity in tumor cells. The results of this study indicate that UCN-01 enhances the progression of tumor cells through S phase thus greatly increasing CPT-induced cytotoxicity. Normal cells, however, are able to arrest in G(0)/G(1) and thus avoid the increased toxicity induced by CPT. Our findings suggest potential usefulness of combining UCN-01 in topoisomerase I inhibitor-based drug therapy for the treatment of breast cancer with a dysfunctional p53 gene.

The role of protein kinase C in the synergistic interaction of safingol and irinotecan in colon cancer cells

“…Second, it is of note that the cell cycle profiles of irinotecan-treated cells were different from those of safingol-treated cells. Irinotecan induced significant increases in the percentage of cells in the G2/M phase, which is consistent with previous findings (29,30), whereas safingol induced significant increases in the apoptotic cell fraction without significantly affecting G2/M phase. These results suggest that safingol and irinotecan acted differently on the cell cycle and in the induction of cell death.…”

Bisindenoisoquinoline Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA Intercalator and Topoisomerase Inhibitor with Antitumor Activity

“…Moreover, cells treated with the bisindenoisoquinoline NSC 727357 tend to arrest at the G 1 phase of the cell cycle compared with NSC 706744 (Fig. 6) or CPT that cause an early G 2 /M block followed by an S-phase arrest (Goldwasser et al, 1996;Shao et al, 1997;Jones et al, 2000). Absence of an S-phase arrest was further supported by lack of significant inhibition of DNA synthesis on treatment with NSC 727357 (Fig.…”

Small-molecule cyclin-dependent kinase modulators

“…As previously mentioned, synergistic effects of UCN-01 have been observed with many chemotherapeutic agents, including mitomycin C, 5-fluorouracil, carmustine, and camptothecin, among others Bunch and Eastman, 1996;Pollack et al, 1996;Husain et al, 1997;Shao et al, 1997;Tsuchida and Urano, 1997;Hsueh et al, 1998;Jones et al, 2000;Sugiyama et al, 2000). Therefore, it is possible that combining UCN-01 with these or other agents could improve its therapeutic index.…”