Chemotherapy and chemosensitization of transgenic mice which express the human multidrug resistance gene in bone marrow: efficacy, potency, and toxicity.
A common form of multidrug resistance in human cancer results from expression of the MDR1 gene which encodes a plasma membrane energy-dependent multidrug efflux pump. We have engineered transgenic mice which express this multidrug transporter in their bone marrow cells and demonstrated that peripheral WBC of these animals provide a rapid and reliable system for assessing the bioactivity of agents that reverse multidrug resistance. Immunocytochemical analysis of bone marrow smears suggests that the activation of the MDR1 transgene has probably occurred at a very early stage of bone marrow differentiation since most bone marrow cells express the transporter. Expression of this transgene in bone marrow produces about 10-fold resistance to leukopenia induced by taxol compared to normal bone marrow. Chemosensitization of MDR1 mice to daunomycin and taxol, measured by a fall in WBC, is detectable at a dose as low as 0.01 mg/kg R-verapamil. A dose of 0.5 mg/kg R-verapamil reduces the WBC by nearly 50%. Chemosensitization of MDR-transgenic mice with 5 mg/kg R-verapamil, which is highly effective in reversing MDR and readily tolerated by mice, necessitates a reduction of the maximum tolerated dose of most chemotherapeutic agents by only 20%. In addition, detailed histopathological examination shows that treatment of mice with chemotherapeutic drugs and R-verapamil does not change the organ-related toxicity pattern but only moderately accentuates inherent toxic side effects of the chemotherapeutic agents. We conclude that MDR1-transgenic mice represent a valid model for evaluating efficacy, potency, and toxicity associated with chemotherapy and chemosensitization of multidrug-resistant cells in animals.
Mickisch
G H
GH
Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Licht
T
T
Merlino
G T
GT
Gottesman
M M
MM
Pastan
I
I
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000633:toxicity; D001853:Bone Marrow / Q000648:ultrastructure*; D003630:Daunorubicin / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity; D004351:Drug Resistance / Q000235:genetics*; D004361:Drug Tolerance; D007422:Intestines / Q000187:drug effects; D007958:Leukocyte Count / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D017239:Paclitaxel; D013154:Spleen / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology / Q000633:toxicity; D014750:Vincristine / Q000494:pharmacology / Q000633:toxicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D008562:Membrane Glycoproteins; D014750:Vincristine; D014747:Vinblastine; D004317:Doxorubicin; D014700:Verapamil; D017239:Paclitaxel; D003630:Daunorubicin