Resistance to taxol chemotherapy produced in mouse marrow cells by safety-modified retroviruses containing a human MDR-1 transcription unit

We used an animal model system to transplant lethally-irradiated mice with one million marrow cells which had been: (1) collected from 5-fluorouracil (5-FU) treated mice; and (2) transduced with retroviruses containing a multiple drug resistance-1 (MDR-1) gene transcription unit. Following recovery from the transplant, we exposed these mice to doses of taxol ranging from 7 mg/kg to 30 mg/kg, which corresponds to doses of 68 to 268 mg/m² in man. The median white blood cell count by 5 days after taxol (expressed as the percentage of the white blood cell count before taxol) was 83% (range 46-100%) in 11 courses of taxol in mice transplanted once with MDR-1 transduced marrow immediately after transplant, whereas the median white blood cell count by 5 days after taxol in mice not transplanted with MDR-1 marrow was 41% in nine courses of taxol (range 11-66%). This difference is statistically different at the P<0.001 level (Wilcoxon test). One million marrow cells from the MDR-1 transplanted mice were harvested and serially transplanted through five additional cohorts of mice, and tested with taxol after each cohort. The white blood cell count (expressed as the percentage of pre-taxol white blood cell count) after each cohort ranged from 94-146% in the 29 mice transplanted with the transduced MDR-1 marrow, which had been through more than one transplant. This is statistically different from the median white blood cell count recovery after taxol in mice which have no human MDR-1 modified marrow (P<0.001). Reverse transcription polymerase chain reaction (RT PCR) analysis showed conclusively that the human MDR-1 cDNA continued to be expressed after four cohorts of transplants, 17 months after the initial transduction and transplant. These data suggest that the vector systems we have used could have modified precursor cells with a capacity for long-term self-renewal and show that the human MDR-1 transcription unit continued to be transcriptionally active with taxol selection in the mouse cells for over 17 months. Thus, such vectors may be of use in protecting hematopoietic cells in patients undergoing taxol treatment from the myelotoxic effects of that therapy.