title: In vivo resistance towards anthracyclines, etoposide, and cis-diamminedichloroplatinum(II).
abstract: From a single wild-type strain of Ehrlich ascites tumor, sublines resistant to daunorubicin, etoposide, and cis-diamminedichloroplatinum(II) have been developed in vivo. Different levels of resistance were achieved after 4 to 8 months for anthracyclines (greater than 32-fold), cis-diamminedichloroplatinum(II) (4-fold), and etoposide (greater than 6-fold). Anthracycline resistance was associated with decreased nuclear steady-state concentration of anthracyclines, increased content of high-molecular-weight 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-diamminedichloroplatinum(II) was accompanied by decreased cis-diamminedichloroplatinum(II)-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. However, cis-diamminedichloroplatinum(II) was curative in anthracycline- and etoposide-resistant cells, as daunorubicin and etoposide were curative in acquired resistance towards cis-diamminedichloroplatinum(II). cis-Diamminedichloroplatinum(II) 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-diamminedichloroplatinum(II) resistance. These in vivo patterns of cross-resistance and collateral sensitivity may be related to observations in clinical chemotherapy.
mesh_terms: D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy*; D002945:Cisplatin / Q000627:therapeutic use*; D003630:Daunorubicin / Q000627:therapeutic use*; D004317:Doxorubicin / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004351:Drug Resistance; D005047:Etoposide / Q000627:therapeutic use*; D007700:Kinetics; D051379:Mice; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship
chemical_list: D005047:Etoposide; D004317:Doxorubicin; D011034:Podophyllotoxin; D002945:Cisplatin; D003630:Daunorubicin