From laboratory expertise to clinical practice: multidrug-resistance-based gene therapy becomes available for urologists.
Many human tumors such as bladder carcinoma that are initially responsive to chemotherapy eventually fail to respond to treatment. For most drugs, 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 expression of the multidrug-resistance (MDR1) gene encoding for P-glycoprotein. In our first set of experiments, we transplanted bone marrow cells derived from transgenic mice that constitutively express MDR1 to lethally irradiated recipients (n = 36). From 6 weeks to 10 months after the transplant, all animals contained MDR1 DNA in spleen and bone marrow specimens as indicated by Southern-blot analysis and expressed MDR1 RNA in bone marrow samples as detected by slot-blot analysis. In addition, these animals were resistant to the myelosuppressive effect of doxorubicin, daunomycin, taxol, vinblastine, vincristine, etoposide, and actinomycin D, whereas control animals that were reconstituted with normal bone marrow reacted with a significant decrease in their white blood counts. In a second set of experiments, we retrovirally transfected a construct consisting of a murine long-terminal repeat (LTR) promoter and the human MDR1 gene into CD34-positive bone marrow stem cells from rhesus monkeys using the same technique as in the ongoing clinical ADA gene-therapy protocol. Upon transplantation, high-level and long-lasting expression of the human MDR1 gene was observed in recipient monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)
Mickisch
G H
GH
Department of Urology, Erasmus University, Rotterdam, The Netherlands.
Schroeder
F H
FH
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D016026:Bone Marrow Transplantation; D003131:Combined Modality Therapy; D004273:DNA, Neoplasm / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015757:Genes, rev / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D000882:Haplorhini; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*
D004273:DNA, Neoplasm; D012334:RNA, Neoplasm