MINOCYCLINE AS A MODULATOR OF CHEMOTHERAPY AND HYPERTHERMIA IN-VITRO AND IN-VIVO

We tested the ability of the collagenase-inhibitor minocycline to incr ease the effectiveness of CDDP, BCNU and mitomycin C +/- hyperthermia. When tested in vitro in FSaIIC fibrosarcoma cells, exposure to minocy cline (100 mu M for 24 h) decreased the CDDP cytotoxicity at 37 degree s C and pH 7.40 in both normally oxygenated and hypoxic cells and decr eased the cytotoxicity of CDDP at 42 degrees C or 43 degrees C in norm ally oxygenated cells while increasing the killing in hypoxic cells. W hen tested at pH 6.45, the presence of minocycline tended to protect b oth normally oxygenated and hypoxic cells from the cytotoxic effects o f CDDP +/- hyperthermia. With exposure to BCNU, minocycline markedly p rotected both normally oxygenated and hypoxic cells at 37 degrees C at both pHs. As the temperature during the exposure to BCNU was increase d to 42 degrees C or 43 degrees C, the protection afforded by minocycl ine diminished especially under low pH conditions where BCNU plus 43 d egrees C was extremely cytotoxic to both normally oxygenated and hypox ic cells. One hour exposure to mitomycin C was more cytotoxic to hypox ic than normally oxygenated cells under all conditions of pH and tempe rature tested and the cytotoxicity of mitomycin C under each condition was increased by minocycline. Both CDDP and BCNU were much more cytot oxic toward FSaIIC tumors in vivo when drug administration was followe d by local heating (43 degrees C, 30 min) of the tumor bearing limb. I n each case, treatment with minocycline had little effect on tumor-cel l killing. Treatment with mitomycin C and hyperthermia resulted in add itive tumor-cell killing, and minocycline administration further incre ased that effect. Tumor-growth delay studies in FSaIIC tumor-bearing a nimals demonstrated that treatment with CDDP, BCNU or mitomycin C prod uced growth delays which were additive with hyperthermia (43 degrees C , 30 min) and/or minocycline administered daily for 14 days on days 4- 18. These results indicate that minocycline, has measurable antitumor and cytotoxic effects under the conditions tested.