A human colon cell line (Ht-29mdrl) made multidrug resistant by infection with an MDR1 retrovirus was used to study reversal of drug resistance in vivo by the anti-P-glycoprotein antibody, MRK-16. The 50% inhibitory concentrations (IC50) of vincristine on Ht-29par and Ht-29mdrl cells was 2.5 and 15ng/ml, respectively. Pretreatment of Ht-29mdrl cells with 10micro g/ml MRK-16 MoAb in vitro resulted in partial restoration of vincristine sensitivity (IC50=7ng/ml). Studies showed that MSTs of mice transplanted ip with 5,000,000 Ht-29par or Ht- 29mdrl were 37 and 39 days respectively. Treatment of mice with 1mg/kg vincristine weekly for three weeks beginning 10 days post-tumor cell injection resulted in a significant increase in MST of the Ht-29par tumor bearing mice (68 days, p<.0001), but had no effect on the Ht-29mdrl mice. However, treatment of mice bearing the Ht-29mdrl tumor with 500micro g MRK-16, before vincristine therapy, reversed resistance to the drug (MST=64 days, p<.0001). The intracavity administration of 454A12 MAB-rRTA (10micro g) to mice bearing OVCAR-3 beginning 10 days post-tumor cell inoculation and then every other day for a total of 10 treatments resulted in a significant increase in MST of 89 days (p<.0001) when compared to the control group (41 days). Coinjection of 50,000 units of rhIFN-alpha and the IT at a similar regimen resulted in 70% long term survival when compared to only 10% survival of mice given the IT alone. The ip injection of 454A12 MAB-rRTA alone or in combination with rhIFN-alpha administered by an identical regimen beginning 15 days post-tumor cell injection resulted in significant (p<.0001) increases in MSTs of 72 and 75 days, respectively. No long term survivors were observed. Multiple treatments of 454A12 MAB-rRTA (10micro g) following cytoreductive therapy, at a time of minimal tumor burden, exhibited a significant increase (p<.0001) in MST of 123 days when compared to the drug treated group alone (MST=76 days). Finally, the combination of the IT and rhIFN-alpha resulted in an enhanced therapeutic response (35% long term survivors) when compared to the IT alone (19%).
