Preparation and utility of a radioiodinated analogue of daunomycin in the study of multidrug resistance.
Anthracyclines are an important class of cytotoxic drugs that are frequently used in cancer chemotherapy, especially in acute leukemia. The pharmacokinetics and disposition of these compounds in whole animals and in cells have been studied employing 3H-labeled forms. However, their usefulness is limited by their low specific activities and the low energy of 3H. Therefore, we have labeled daunomycin using 125I-Bolton-Hunter reagent. The resultant anthracycline analogue, iodomycin, has a specific activity of approximately 2000 Ci/mmol. Although this compound was 10-fold less toxic to normal cells than daunomycin, multidrug-resistant cells were cross-resistant to it. Like other drugs to which these cells are cross-resistant, its accumulation by them was greatly reduced, compared with drug-sensitive cells. We have also utilized this compound in photoaffinity labeling experiments to identify its target in multidrug-resistant cells. We observed the specific binding of iodomycin to P-glycoprotein in membrane vesicles as well as in intact cells, thereby directly demonstrating that this protein specifically binds anthracyclines as well as Vinca alkaloids.
Busche
R
R
Zentrum Biochemie II, Abt. Biophysikalische Chemie, Medizinische Hochschule Hannover, West Germany.
Tümmler
B
B
Riordan
J R
JR
Cano-Gauci
D F
DF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000345:Affinity Labels; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D006224:Cricetinae; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; C060588:iodomycin; D000255:Adenosine Triphosphate; D003630:Daunorubicin