IN-VIVO MODULATION OF SEVERAL ANTICANCER AGENTS BY BETA-CAROTENE

The ability of the collagenase inhibitor minocycline and of beta-carot ene to act as positive modulators of cytotoxic anticancer agents was a ssessed in vitro and in vivo. Cell-culture studies were conducted usin g the human SCC-25 squamous carcinoma cell line. Simultaneous exposure of the cells to minocycline and beta-carotene or 13-cis-retinoic acid along with cisplatin (CDDP) resulted in a small decrease in the cytot oxicity of the CDDP. The addition of each of the modulator combination s for 1 h or 24 h to treatment with melphalan (L-PAM) or carmustine (B CNU) resulted in greater-than-additive cytotoxicity with each of four regimens. The modulator combinations of minocycline and beta-carotene applied for 1 h or 24 h and the modulator combination of minocycline a nd 13-cis-retinoic acid produced greater-than-additive cytotoxicity at 50 mu M 4-hydroperoxycyclophosphamide (4-HC), whereas minocycline and 13-cis-retinoic acid applied for 1 h was antagonistic with 4-HC and t he other modulator treatments at low concentrations of 4-HC resulted i n subadditive cytotoxicity. The effect of treatment with beta-carotene alone and in combination with several different anticancer agents was examined in two murine solid tumors, the FSaII fibrosarcoma and the S CC VII carcinoma. Administration of the modulators alone or in combina tion did not alter the growth of either tumor. Whereas increases in tu mor growth delay occurred with the antitumor alkylating agents and bet a-carotene and with minocycline and beta-carotene, a diminution in tum or growth delay was produced by 5-fluorouracil in the presence of thes e modulators. The modulator combination also resulted in increased tum or growth delay with Adriamycin and etoposide. Tumor-cell, survival as say showed increased killing of FSaII tumor cells with the modulator c ombination and melphalan or cyclophosphamide as compared with the drug s alone. These results indicate that further investigation of this mod ulator strategy is warranted.