Establishing chemoresistance in hematopoietic progenitor cells.
An attractive approach to circumvent chemotherapy-induced myelosuppression is the use of gene-transfer technology to introduce new genetic material into hematopoietic cells. Several pre-clinical studies have demonstrated that increasing the expression of genes encoding proteins that modulate drug resistance in hematopoietic cells provides significant protection against chemotherapy-induced myelosuppression both in vitro and in vivo. Most work in this area has focused on the use of recombinant retroviruses as vectors for the delivery of DNA sequences into hematopoietic stem cells and progenitor cells. Based on these studies, clinical trials are now under way to evaluate the potential use of two gene sequences-multidrug resistance gene 1 and O6-methylguanine DNA methyltransferase. Reducing chemotherapy-induced myelosuppression by increasing the expression of genes that modulate drug resistance via gene transfer into bone marrow cells might allow dose-intensification of chemotherapy, which might result in an improvement in the clinical outcome of patients with high-risk tumors.
Maze
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Section of Pediatric Hematology Oncology, Herman B. Wells Center for Pediatric Research, James Whitcomb Riley Hospital for Children, Indianapolis, IN 46202, USA.
Hanenberg
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Williams
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D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000818:Animals; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics* / Q000502:physiology; D005353:Fibronectins / Q000235:genetics; D018014:Gene Transfer Techniques / Q000639:trends; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005982:Glutathione Transferase / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D008780:Methyltransferases / Q000235:genetics; D051379:Mice; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
D005353:Fibronectins; D000444:Aldehyde Dehydrogenase; D013762:Tetrahydrofolate Dehydrogenase; D008780:Methyltransferases; D005982:Glutathione Transferase