Many human tumors such as bladder carcinoma that are initially responsive to chemotherapy eventually fail to respond to treatment. For most drugs, the dose escalation that may be required for a cure cannot be achieved because sensitive tissues such as bone marrow limit cytotoxic therapy. Approaches to prevent or circumvent myelosuppression are therefore a high priority of research on dose intensification protocols. One such strategy is to protect bone marrow cells by virtue of drug resistance gene expression such as the MDR1 gene encoding for P-glycoprotein. In a first set of experiments, bone marrow cells derived from transgenic mice that constitutively express MDR1 were transplanted to lethally irradiated mouse-recipients. In a second set of experiments, a construct consisting of a murine LTR promoter, the delta mouse molony promoter, and the human MDR1 gene was transfected into CD34-positive bone marrow stem cells from rhesus monkeys. The mouse studies demonstrated effective and long-lasting protection against chemotherapy-induced myelosuppression. Furthermore, high and stable expression of the human MDR1 gene was observed in recipient monkey bone marrow cells. On the basis of this preclinical analysis, clinical protocols to test myeloprotection afforded by MDR1 gene transfer so as to intensify chemotherapy in otherwise incurable human cancer were submitted for institutional and state approval. The protocol "phase I study of autologous reinfusion of haematopoietic precursor cells genetically modified by retroviral gene transfer of the multidrug resistance (MDR1) gene in patients with metastatic refractory bladder carcinoma (no. MEC 133.184/1994/54)" has been activated for production of virus supernatant.

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Aktuelle Urologie
Erasmus MC: University Medical Center Rotterdam

Mickisch, G. H. J. (1996). Clinical Gene Therapy Using the Human MDR1 Gene: At the Threshold. Aktuelle Urologie, 27, 72–75. doi:10.1055/s-2008-1055660