Minocycline as a modulator of chemotherapy and hyperthermia in vitro and in vivo.
We tested the ability of the collagenase-inhibitor minocycline to increase the effectiveness of CDDP, BCNU and mitomycin C +/- hyperthermia. When tested in vitro in FSaIIC fibrosarcoma cells, exposure to minocycline (100 microM for 24 h) decreased the CDDP cytotoxicity at 37 degrees C and pH 7.40 in both normally oxygenated and hypoxic cells and decreased the cytotoxicity of CDDP at 42 degrees C or 43 degrees C in normally oxygenated cells while increasing the killing in hypoxic cells. When tested at pH 6.45, the presence of minocycline tended to protect both normally oxygenated and hypoxic cells from the cytotoxic effects of CDDP +/- hyperthermia. With exposure to BCNU, minocycline markedly protected both normally oxygenated and hypoxic cells at 37 degrees C at both pHs. As the temperature during the exposure to BCNU was increased to 42 degrees C or 43 degrees C, the protection afforded by minocycline diminished especially under low pH conditions where BCNU plus 43 degrees C was extremely cytotoxic to both normally oxygenated and hypoxic cells. One hour exposure to mitomycin C was more cytotoxic to hypoxic than normally oxygenated cells under all conditions of pH and temperature tested and the cytotoxicity of mitomycin C under each condition was increased by minocycline. Both CDDP and BCNU were much more cytotoxic toward FSaIIC tumors in vivo when drug administration was followed by local heating (43 degrees C, 30 min) of the tumor bearing limb. In each case, treatment with minocycline had little effect on tumor-cell killing. Treatment with mitomycin C and hyperthermia resulted in additive tumor-cell killing, and minocycline administration further increased that effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Dana-Farber Cancer Institute, Boston, MA 02115.
B A
BA
Teicher
S A
SA
Holden
C J
CJ
Liu
G
G
Ara
T S
TS
Herman
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002330:Carmustine / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D006979:Hyperthermia, Induced; D051379:Mice; D008809:Mice, Inbred C3H; D008911:Minocycline / Q000494:pharmacology*; D016685:Mitomycin / Q000008:administration & dosage; D012513:Sarcoma, Experimental / Q000628:therapy*; D014407:Tumor Cells, Cultured
D016685:Mitomycin; D008911:Minocycline; D002945:Cisplatin; D002330:Carmustine