SEQUENCE-DEPENDENT MODULATION OF ANTICANCER DRUG ACTIVITIES BY 7-ETHYL-10-HYDROXYCAMPTOTHECIN IN AN HST-1 HUMAN SQUAMOUS CARCINOMA CELL-LINE

Background: We studied the modulatory effects of 7-ethyl-10-hydroxy-ca mpothecin (SN-38), an active metabolite of 7-ethyl-10-[4-(1-piperidino )-1-piperidino] carbonyloxycamptothecin, on the antitumor activities o f clinically important anticancer drugs including cisplatin (CDDP), 5- fluorouracil (5-FU), mitomycin C (MMC), etoposide (VP-16), and adriamy cin (ADR). Materials and Methods: The HST-1 human carcinoma cells were treated with graded concentrations of these anticancer drugs either a lone or in combination with IC50 concentration of SN-38, administered in several different treatment schedules, and antitumor activity was e valuated by the growth inhibition assay. Results: SN-38 potentiated th e antitumor activity of CDDP in all schedules with a maximal effect ob served with a simultaneous administration, while SN-38 enhanced the cy totoxicity of MMC, 5-FU, or VP-16 only in certain schedules. By contra st, SN-38 attenuated the anticancer effect of ADR in all schedules. Co nclusions: These results demonstrate that SN-38 may have the advantage of augmenting the anticancer activity in combination with CDDP, MMC, 5-FU, and VP-16, depending on the schedule of administration, and shou ld thus be incorporated into the design of a clinical trial for obtain ing maximal therapeutic synergy. Background: We studied the modulatory effects of 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabol ite of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothe cin, on the antitumor activities of clinically important anticancer dr ugs including cisplatin (CDDP), 5-fluorouracil (5-FU), mitomycin C (MM C), etoposide (VP-16), and adriamycin (ADR). Materials and Methods: Th e HST-1 human carcinoma cells were treated with graded concentrations of these anticancer drugs either alone or in combination with IC50 con centration of SN-38, administered in several different treatment sched ules, and antitumor activity was evaluated by the growth inhibition as say. Results: SN-38 potentiated the antitumor activity of CDDP in all schedules with a maximal effect observed with a simultaneous administr ation, while SN-38 enhanced the cytotoxicity of MMC, 5-FU, or VP-16 on ly in certain schedules. By contrast, SN-38 attenuated the anticancer effect of ADR in all schedules. Conclusions: These results demonstrate that SN-38 may have the advantage of augmenting the anticancer activi ty in combination with CDDP, MMC, 5-FU, and VP-16, depending on the sc hedule of administration, and should thus be incorporated into the des ign of a clinical trial for obtaining maximal therapeutic synergy.