isotretinoin and Fibrosarcoma

The ability of the collagenase inhibitor minocycline and of beta-carotene to act as positive modulators of cytotoxic anticancer agents was assessed in vitro and in vivo. Cell-culture studies were conducted using 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 cytotoxicity of the CDDP. The addition of each of the modulator combinations for 1 h or 24 h to treatment with melphalan (L-PAM) or carmustine (BCNU) 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 and 13-cis-retinoic acid produced greater-than-additive cytotoxicity at 50 microM 4-hydroperoxycyclophosphamide (4-HC), whereas minocycline and 13-cis-retinoic acid applied for 1 h was antagonistic with 4-HC and the other modulator treatments at low concentrations of 4-HC resulted in 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 SCC VII carcinoma. Administration of the modulators alone or in combination did not alter the growth of either tumor. Whereas increases in tumor growth delay occurred with the antitumor alkylating agents and beta-carotene and with minocycline and beta-carotene, a diminution in tumor growth delay was produced by 5-fluorouracil in the presence of these modulators. The modulator combination also resulted in increased tumor growth delay with adriamycin and etoposide. Tumor-cell survival assay showed increased killing of FSaII tumor cells with the modulator combination and melphalan or cyclophosphamide as compared with the drugs alone. These results indicate that further investigation of this modulator strategy is warranted.

Topics: Animals; Antineoplastic Agents; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Dose-Response Relationship, Drug; Drug Interactions; Fibrosarcoma; Humans; Isotretinoin; Male; Mice; Mice, Inbred C3H; Minocycline; Tumor Cells, Cultured

The effects of various retinoids and dexamethasone on protein and type IV collagen synthesis were studied in human basement membrane-forming fibrosarcoma (HT-1080) cells. Retinol, etretinate (Ro-10-9359), free acid of etretinate (Ro-10-1670) and 13-cis-retinoic acid (RA) in 10(-7) M concentrations slightly reduced total protein and type IV collagen synthesis in the HT-1080 cells, the largest decrease being found with Ro-10-1670 and 13-cis-RA. In contrast, dexamethasone markedly stimulated the incorporation of [14C]proline and the synthesis of [14C]hydroxyproline, an index of the synthesis of type IV collagen. Part of the increase noted in total protein synthesis and type IV collagen synthesis after dexamethasone was due to enhanced intracellular activity of proline. Retinoids did not markedly affect the specific activity of proline. The addition of 13-cis-RA with dexamethasone also increased total protein and type IV collagen synthesis, but to a lesser extent than did dexamethasone alone. 13-cis-RA did not affect the synthesis of fibronectin, a component of connective tissue matrix, while dexamethasone clearly increased the absolute and relative synthesis of fibronectin. Thus the results indicate that retinoids modulate the metabolism of HT-1080 cells, in a way which is separate from that of glucocorticoids. It is also possible that retinoids used in vivo in clinical practice may modulate the metabolism of the connective tissue matrix of basement membranes, i.e. type IV collagen.

Topics: Acitretin; Collagen; Dexamethasone; Electrophoresis, Starch Gel; Etretinate; Fibronectins; Fibrosarcoma; Isotretinoin; Retinoids; Tretinoin; Tumor Cells, Cultured; Vitamin A