Activity of the pyrazoloacridines against multidrug-resistant tumor cells.
A series of 2-aminoalkyl-5-nitropyrazolo [3,4,5-kl]acridines (pyrazoloacridines) were tested in vitro against a panel of multidrug-resistant cell lines comprising Adriamycin-resistant P388 leukemia, B16 melanoma, and mammary adenocarcinoma 16c. This new class of anticancer agents, particularly the 9-substituted methoxy derivatives, exhibited significant activity against all of the lines tested. The degree of cross-resistance to these compounds ranged from zero to 8-fold in the 138-fold Adriamycin-resistant P388/ADR line and was greatly diminished in the B16/ADR and 16c/ADR lines. Selected pyrazoloacridines were subsequently tested in vivo against B16 and B16/ADR cells established as solid tumors from the tissue culture line and shown to retain a significant degree of Adriamycin resistance. Whereas the B16/ADR line exhibited 2 logs less net tumor-cell kill than the B16 parent in response to Adriamycin treatment, the resistant tumor was completely sensitive to the pyrazoloacridines tested and proved in some experiments to be collaterally sensitive. The favorable activity of the pyrazoloacridines against these Adriamycin-resistant tumor lines points to the potential efficacy of these compounds against multidrug-resistant tumors encountered clinically.
Sebolt
J
J
Pharmacology Department, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Havlick
M
M
Hamelehle
K
K
Nelson
J
J
Leopold
W
W
Jackson
R
R
D000166:Acridines / Q000494:pharmacology* / Q000627:therapeutic use; D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D007364:Intercalating Agents / Q000627:therapeutic use; D007941:Leukemia P388 / Q000473:pathology*; D007942:Leukemia, Experimental / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use
D000166:Acridines; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D011720:Pyrazoles; D014750:Vincristine; D004317:Doxorubicin