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-flu orouracil (5-FU) treated mice; and (2) transduced with retroviruses co ntaining a multiple drug resistance-1 (MDR-1) gene transcription unit. Following recovery from the transplant, we exposed these mice to dose s of taxol ranging from 7 mg/kg to 30 mg/kg, which corresponds to dose s of 68 to 268 mg/m(2) 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 cours es of taxol (range 11-66%). This difference is statistically different at the P<0.001 level (Wilcoxon test). One million marrow cells from t he MDR-1 transplanted mice were harvested and serially transplanted th rough five additional cohorts of mice, and tested with taxol after eac h cohort. The white blood cell count (expressed as the percentage of p re-taxol white blood cell count) after each cohort ranged from 94-146% in the 29 mice transplanted with the transduced MDR-1 marrow, which h ad been through more than one transplant. This is statistically differ ent from the median white blood cell count recovery after taxol in mic e which have no human MDR-1 modified marrow (P<0.001). Reverse transcr iption polymerase chain reaction (RT PCR) analysis showed conclusively that the human MDR-1 cDNA continued to be expressed after four cohort s of transplants, 17 months after the initial transduction and transpl ant. These data suggest that the vector systems we have used could hav e modified precursor cells with a capacity for long-term self-renewal and show that the human MDR-1 transcription unit continued to be trans criptionally active with taxol selection in the mouse cells for over 1 7 months. Thus, such vectors may be of use in protecting hematopoietic cells in patients undergoing taxol treatment from the myelotoxic effe cts of that therapy.