Isolation of a taxol-resistant Leishmania donovani promastigote mutant that exhibits a multidrug-resistant phenotype.
We raised a strain of Leishmania donovani in the laboratory that was resistant to 500 nM taxol. The IC50 of the wild-type strain for taxol was 35 nM and that of the taxol-resistant strain (T-500) was 1 microM. The T-500 strain exhibited a Mdr phenotype; it was also resistant to other unrelated drugs like vinblastine, adriamycin and the commonly used antimonial drugs pentostam and glucantime. Verapamil (20 nM), a calcium channel blocker, was found to reverse the resistance of T-500 to taxol. Acquired resistance to taxol has been reported to be mediated by alterations involving tubulin in cancer cells. Thus polymerisation assays with tubulin fractions in wild-type versus taxol-resistant cells (T-500) were performed in vitro. The tubulin fraction from T-500 was more resistant to in vitro polymerisation than the tubulin isolated from the wild-type, suggesting that this is one means by which the parasite may acquire resistance to taxol.
Kapoor
P
P
School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
Ghosh
A
A
Madhubala
R
R
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D007893:Leishmania donovani / Q000187:drug effects* / Q000235:genetics; D009154:Mutation; D017239:Paclitaxel / Q000494:pharmacology*; D010641:Phenotype; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D000981:Antiprotozoal Agents; D002121:Calcium Channel Blockers; D014404:Tubulin; D004317:Doxorubicin; D014700:Verapamil; D017239:Paclitaxel