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).