Reversal of Drug Resistance in a Human Colon Cancer Xenograft Expressing MDR1 Complementary DNA by In Vivo Administration of MRK-16 Monoclonal Antibody

Abstract

One strategy to overcome multidrug resistance in neoplasia is to inhibit the gpl7O glycoprotein (relative molecular mass, 170 000) that functions as a plasma membrane, energy-dependent, drug-ef flux pump. The human colon cancer cell line HT-29, which grows as an as citic tumor in athymic NCr-nu/nu nude mice, was made multidrug resistant by infection with an MDR1 (also known as PGY1) retrovirus. Referred to as HT-29 ^mdr1 , it was used to study reversal of drug resistance in vivo by the anti-P-glycoprotein monoclonal antibody MRK-16. Flow cytometry and radioimmunoassay demonstrated a marked increase in MRK-16 reactivity on HT-29 ^mdr1 cells as compared with its reactivity on the parental, uninfected cell line (HT-29 ^par The 50% in hibitory concentrations (IC ₅₀ ) of vincristine on HT-29 ^par and HT-29 ^mdr1 cells were 2.5 and 15 ng/niL, respectively. The MRK-16 monoclonal antibody did not affect the vincristine sensitivity of the HT-29 ^par cells. Pretreatment of HT-29 ^mdr1 cells with 10 μg/mL MRK-16 in tissue culture partially restored the vincristine sensitivity (IC ₅₀ = 7 ng/mL). This modulation of vincristine sensitivity by MRK-16 was then tested in vivo. The median survival times of mice given in traperitoneal transplants of 5 × 10 ⁶ HT-29 ^par or HT-29 ^mdr1 were 37 and 39 days, respectively. Treatment of mice with 1 mg/kg vincristine weekly for 3 weeks, beginning 10 days after tumor injection, resulted in a significant increase in the median survival time of the HT-29 ^par tumor-bearing mice (68 days, P.<.0001) but it had no effect on the HT-29 ^mdr1 tumor-bearing mice. However, treatment of mice bearing the HT-29 ^mdr1 tumor with MRK-16 before vincristine therapy reversed the resistance to the drug (median survival time = 64 days, P<.0001) The MRK-16 monoclonal antibody alone had no effect on the median survival time of mice given an injection of either HT-29 ^par or HT-29 ^mdr1 cells. These results suggest that strategies employing monoclonal antibody against gpl70 may be clinically useful to reverse multidrug resistance. [J Natl Cancer Inst 83:1386–1391, 1991]