The Retention or Efltux of Phthalanilide (NSC 60339)-Lipid Complexes by Sensitive or Resistant Murine Tumor Cells and Escherichia coli

The retention and efflux of lipid-bound 2-chloro-4',4"-di(2imidazolin-2-yl)terephthalanilide (NSC 60339) has been correlated with the sensitivity, resistance, or cross-resistance of 7 tumor lines to phthalanilide treatment in vivo. The sensitive tumors (L1210, L1210/MTX, L1210/ara-C, and P815) rapidly took up the drug and retained it primarily as lipid-bound drug for the 24-hr experimental period. The resistant tumor, L1210/ NSC 60339, and 2 cross-resistant tumors, P388/VCR and P815/VLB, took up as much drug as the sensitive tumors did by 0.5 hr, but there was an efflux of lipid-bound drug from these resistant tumors by 24 hr. Two other drug fractions, hydrophilic-bound and "free," generally decreased in both sensitive and resistant tumors. All 3 drug fractions are extracted from Escherichia coli B, P388, and P388/NSC 60339 that were treated in. vitro, and the efflux of drug from these tumor cells in vitro are described. The drug-lipid complexes which were extracted from phthalanilide-resistant and cross-resistant tumors after treatment in vivo were more hydrophobic than those from sensitive tumors. The relative hydrophobicity of the crude drug complexes from P388 and P388/60339 cells was similar to the relative hydrophobicity of highly purified complexes. The drug-lipid complexes from the 2 phthalanilidesensitive tumors, which were resistant to Methotrexate (MTX) and cytosine arabinoside (ara-C), did not show such hydrophobic character. Therefore, it is possible that the mechanism of resistance to Vinca alkaloids, which are cross-resistant to the phthalanilides and are also large cationic drugs, may involve the formation and mobilization of drug-lipid complexes.