Resistance mechanisms in murine tumors with acquired multidrug resistance.
Mechanisms of multidrug resistance were studied in murine leukemia (L 1210) and sarcoma (Sa 180) tumors after pretreatment with anthracyclines in vivo. Despite identical pretreatment protocols, a considerable difference in the level of resistance between L 1210 and Sa 180 tumors was noted (for doxorubicin: 45-fold versus 340-fold; for daunorubicin: 51-fold versus 275-fold). However, no difference in mdr 1 gene-amplification and the overexpression of mdr 1-RNA or P-glycoprotein was demonstrated. None of these parameters did increase by further treatment with a higher concentration of anthracyclines. Resistant sublines of Sa 180 revealed an overexpression of glutathione S-transferase-pi (GST-pi) in comparison to the parental line, whereas in sensitive and resistant sublines of L 1210 tumors the expression of GST-pi was similar. In order to study whether trifluoperazine can reverse the P-glycoprotein mediated component of multidrug resistance, trifluoperazine and doxorubicin were tested in vitro in L 1210 and Sa 180 cells. In contrast to the complete reversal of resistance in L 1210 tumors, resistance in Sa 180 was only partly circumvented. However, by buthionine sulfoximine treatment, the toxicity of multidrug resistant Sa 180 tumors could be increased. It was possible to reverse the resistance of Sa 180 tumors completely by trifluoperazine plus buthionine sulfoximine. Thus, multidrug-resistant Sa 180 tumors express different defense mechanisms whereas L 1210 tumors express only one defense mechanism (P-glycoprotein).
Volm
M
M
Department of Experimental Pathology, German Cancer Research Center, Heidelberg.
Efferth
T
T
Mattern
J
J
Pommerenke
E W
EW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D015139:Blotting, Southern; D004351:Drug Resistance / Q000235:genetics*; D007150:Immunohistochemistry; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D012510:Sarcoma 180 / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents