Multidrug resistance modulator - zosuquidar
P-glycoproteins (Pgps) are implicated in multidrug resistance in cancer patients. Two forms of Pgp are known, and it is the class I form that is involved in the development of multidrug resistance. The overexpression of Pgps confers the MDR resistance phenotype to tumour cells.
Class I Pgps are expressed by the MDR-1 gene, and overexpression of this gene has been seen at diagnosis in various cancers, including colon and kidney, and after relapse or treatment failure in others, notably breast cancer, leukaemia and lymphoma. Pgp acts as a transporter for the drugs, removing them from the tumour, and this action has been seen in a variety of structurally dissimilar drugs, including doxorubicin, etoposide, Taxol and vinblastine. In 1981, it was found that the non-cytotoxic calcium channel blocker verapamil could overcome the MDR phenotype to vinblastine and vincristine, and this started the search for an effective non-cytotoxic that would resensitise MDR cells to anticancer agents.
Lilly has identified zosuquidar as a potential MDR modulator. It has a high affinity to Pgp, and no other pharmacological effects have been observed.1 A number of Phase I studies investigating the efficacy, safety and tolerability of zosuquidar in combination with a variety of anticancer agents have been carried out. These include doxorubicin, docetaxel, paclitaxel, vinorelbine and daunorubicin. Subsequently, a Phase II trial looked at its effect in patients with newly-diagnosed high risk acute myeloid leukaemia.2
A total of 52 patients were given a continuous IV infusion of zosuquidar, either 480mg/m2 over 96 hours, or 320mg/m2 over 72 hours. This was given in combination with doses of daunorubicin for the first days, and high dose cytarabine for the next four.
The response could be evaluated in 39 of the patients. Fifteen of these had a complete response, nine a partial complete response, five a partial response, and a total of 10 patients were refractory.
An analysis of Pgp function in bone marrow mononuclear cells of 45 patients indicated that 90% of the samples that showed Pgp modulation before dosing with zosuquidar exhibited Pgp inhibition afterwards.
Numerous randomised placebo controlled double blind Phase III trials are being carried out to look at zosuquidar in combination with a variety of different anticancer agents, notably those with acute myeloid leukaemia.
1. D. Vo, M.W. Wolowyk and E.E. Knaus, Drug Des. Discov. 1992. 9. 69
2. L.D. Cripe et al. Blood 2001, 98 (11, Part 1): Abst 2492