Transfer of drug resistance genes in hematopoietic progenitors for chemoprotection: is it still an option?
For numerous malignancies a relationship between the intensity of antineoplastic chemotherapy and tumor response has been demonstrated. Myelotoxicity is the main cause of chemotherapy-associated morbidity and of treatment delays. The concept of myeloprotective cytostatic drug resistance gene transfer to normal hematopoietic stem cells (HSC) therefore sparks great enthusiasm. While initial studies using murine retroviral vectors on murine HSC showed that the concept works, a number of clinical studies in the last decade were not informative because of limitations in transduction efficiency and transgene expression.Furthermore, possible side effects such as unforeseen transgene activity and vector integration-based leukemogenesis have been reported. Among others, these developments raised some scepticism against the feasibility of myeloprotective gene transfer. Recently, considerable improvements have been achieved in vector design, HSC manipulation, selection protocols and risk assessment methods which are discussed in detail here. Based on these experimental studies successful clinical trials can now be anticipated.
Laufs
S
S
Research Program Innovative Cancer Diagnostics and Therapy, German Cancer Research Center, Heidelberg, Germany.
Buss
E C
EC
Zeller
W J
WJ
Fruehauf
S
S
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D018014:Gene Transfer Techniques / Q000639:trends*; D015316:Genetic Therapy / Q000009:adverse effects / Q000639:trends*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D016254:Mutagenesis, Insertional / Q000235:genetics; D018570:Risk Assessment; D019076:Transgenes / Q000235:genetics*
D000970:Antineoplastic Agents