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Background: The synthetic 4’-O-benzylated doxorubicin analog WP744 was designed to abrogate transport by the multidrug resistance (MDR)-associated ATP-binding cassette (ABC) proteins P-glycoprotein (Pgp) and multidrug resistance protein (MRP-1). We compared its uptake and cytotoxicity with those of doxorubicin and daunorubicin in cell lines overexpressing Pgp, MRP-1 or breast cancer resistance protein (BCRP) and in acute myeloid leukemia (AML) cells. Methods: Cellular uptake was studied by flow cytometry and cytotoxicity in 96-h 96-well cultures in cell lines overexpressing Pgp, MRP-1 or wild type (BCRPR482) or mutant (BCRPR482T, BCRPR482G) BCRP and in pre-treatment AML marrow cells. Results: Uptake and cytotoxicity of WP744 were consistently greater than those of doxorubicin and daunorubicin at equimolar concentrations in all cell lines studied and in AML cells. Conclusion: WP744 overcomes transport by Pgp, MRP-1 and BCRP in cell lines and AML cells and is a promising agent for clinical development in AML and other malignancies with broad-spectrum multidrug resistance.

Background: The taxane paclitaxel (Taxol) is often of limited efficacy in chemotherapeutic regimens because some cancer cells express high levels of the efflux pump, P-glycoprotein (Pgp), which removes the drug from the cells. The orally active paclitaxel analog IDN-5109 has been reported to overcome Pgp-mediated drug resistance. We tested whether IDN-5109 acts by modulating Pgp activity. Methods: Human MDA435/LCC6 mdr1 and MDA435/LCC6 breast carcinoma cells, which express and do not express Pgp, respectively, were incubated with [ 3 H]IDN-5109 and paclitaxel to determine intracellular drug accumulation. Flow cytometry was used to analyze intracellular retention of two Pgp substrates, rhodamine 123 (Rh-123) and doxorubicin, in both breast carcinoma cell lines and in human colon carcinoma cells (SW-620, DLD 1 , and HCT-15, whose Pgp levels vary) treated with different taxanes. The effects of IDN-5109 and paclitaxel on tumor growth in vivo were studied with the use of tumors established through xenografts of Pgp-expressing SW-620 and DLD 1 cells in severe combined immunodeficiency mice. All statistical tests were two-sided. Results: Pgp-expressing cells treated with IDN-5109 or with the taxane-based drug resistance reversal agent tRA96023, which blocks Pgp activity, retained 8.1- and 9.4-fold more Rh-123 (P = .0001), respectively, and 1.7- and 1.9-fold more doxo-rubicin (P = .001), respectively, than cells treated with paclitaxel. Non-Pgp-expressing cells treated similarly demonstrated no increased retention of either substrate. MDA435/ LCC6 mdr1 cells retained 5.3-fold more [ 3 H]IDN-5109 than [ 3 H]paclitaxel after 2 hours (P = .01). IDN-5109 showed statistically significantly higher tumor growth inhibition than paclitaxel against the SW-620 xenograft (P = .003). Conclusions: IDN-5109 modulates Pgp activity, resulting in superior tumor growth inhibition against Pgp-expressing tumors as compared with paclitaxel. IDN-5109 may broaden the spectrum of taxane use to include colon tumors.

Purpose: To determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLT) and the pharmacokinetics of BAY59, a novel taxane given as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory solid tumors. Experimental Design: Initially, 15 patients with previously treated (median of 4 prior chemotherapy regimens) refractory cancers, but with normal marrow, hepatic and renal function were treated with BAY59 at doses of 15, 30, 50, 75 and 100 mg/m2 using a standard dose escalation design. Subsequently, 11 patients were treated, 5 at 90 mg/m2 and 6 who had had prior oxaliplatin at 75 mg/m2. Results: At 75 mg/m2, grade 4 neutropenia was noted in 2/6 patients, of whom 1 had grade 4 neutropenia lasting more than 5 days (DLT). At 100 mg/m2, 2/2 patients had febrile neutropenia, with 1 fatality. At 90 mg/m2, 2/5 patients had DLTs, including grade 3 neuropathy, severe lower extremity pain, dehydration and grade 4 neutropenia. The MTD was determined to be 75 mg/m2. A cohort of 6 patients, previously exposed to oxaliplatin, were enrolled at the MTD to evaluate the incidence of neurotoxicity. While DLTs (grade 3 arthralgia, grade 4 neutropenia) were noted in 3/6 patients, there was no increase in the incidence of neurotoxicity. There were no responses. Pharmacokinetics of BAY59 was linear over the doses studied, with a median terminal half-life of 21 h. Conclusions: The recommended phase II dose for BAY59 is 75 mg/m2.