The aims of this study were to evaluate the interaction of topotecan with adriamycin, etoposide, 5 fluorouracil (5 FU) and mitomycin C in the established four ovarian cancer cell lines and three cervical cancer cell lines and to establish whether the combination of topotecan with other antitumor drugs would be a synergism for chemotherapy in patients with ovarian and cervical cancer.

Five antitumor drugs were tested for synergism and antagonism in combination studies in four ovarian cancer cell lines (A2780, A2780 cisplatin resistant variant, A2780 taxol resistant variant, SKOV3) and three cervical cancer cell lines (HeLa, SiHa, ME180). Cytotoxic effects were determined by MTT assay. Synergic interaction was calculated by the median effect principle in which combination index (CI) of less than one suggest a synergic interaction.

Dm value of topotecan against SKOV3 (2.07 ug/ml), HeLa (3.32 ug/ml), SiHa cell lines (2.5 ug/ml) were above peak plasma concentration of topotecan (0.5 ug/ml) but most antitumor drugs tested in combinations index were within clinically relevant range. Combination with topotecan showed a synergic effect (CI<1) in seven cancer cell lines at a intermediate or high level of cytotoxicity especially with mitomycin C (6/7), etoposide (6/7), 5 FU (6/7) and adriamycin (4/7). Most striking findings were that a synergic effect was shown in all ovarian cancer cell lines to topotecan/mitomycin C, topotecan/5 FU and topotecan/esoposide combination showed a synergic effect in all cervical cancer cell lines. Topotecan/adriamycin combination showed synergism at an intermediate or high level of cytotoxicity in cisplatin or Taxol resistant ovarian cancer cell lines (A2780CP, A2780TX, SKOV3).

These results suggested that topotecan showed a synergic effect with a wide range of antitumor drugs: adriamycin, etoposide, 5 FU, mitomycin C in ovarian and cervical cancer cell lines. Combinations of topotecan/mitomycin C, topotecan/5 FU and topotecan/adriamycin for ovarian cancer and a combination of topotecan/etoposide for cervical cancer seemed worthy of consideration for clinical application.