INVIVO RESISTANCE TOWARDS ANTHRACYCLINES, ETOPOSIDE, AND CIS-DIAMMINEDICHLOROPLATINUM(II)

Abstract

From a single wild-type strain of Ehrlich ascites tumor [mouse], sublines resistant to daunorubicin, etoposide and cis-diamminedichloroplatinum(II) [cis-DDP] was developed in vivo. Different levels of resistance were achieved after 4-8 mo. for anthracyclines (> 32-fold), cis-DDP (4-fold), and etoposide (> 6-fold). Anthracycline resistance was associated with decreased nuclear steady-state concentration of anthracyclines, increased content of high-MW membrane glycoproteins, and glucose-dependent drug extrusion after metabolic blockade with sodium azide. A similar pump system which was apparently not drug specific was also documented in etoposide resistance. Resistance towards cis-DDP was accompanied by decreased cis-DDP-induced DNA damage in vitro when proteinase K-resistant interstrand cross-links were measured by alkaline elution. Parallel in vivo studies revealed cross-resistance of various degrees among a number of anthracycline analogs, complete cross-resistance among daunorubicin, doxorubicin and 4''-(9-acridinylamino)methanesulfon-M-anisidine (amsacrine), and partial cross-resistance between daunorubicin and etoposide. cis-DDP was curative in anthracycline- and etoposide-resistant cells, as daunorubicin and etoposide were curative in acquired resistance towards cis-DDP. cis-DDP resistance was also overcome by the derivative 1,2,diaminocyclohexylplatinum malonate. The Vinca alkaloid vindesine, although only marginally active in the control tumor, was highly active in cells selected for cis-DDP resistance. These in vivo patterns of cross-resistance and collateral sensitivity may be related to observations in clinical chemotherapy.