Gene transfer-mediated generation of drug-resistant hemopoiesis.
Autologous- or allogeneic-bone marrow transplantation are increasingly used to overcome the myelosuppressive effects of high dose chemotherapy administered to cancer patients. Transfer of the multidrug resistance (MDR) gene in hemopoietic progenitors has been proposed as a tool to administer higher and possibly more curative doses of chemotherapy. Murine models have demonstrated that retrovirus-mediated MDR transfer in bone marrow cells can render animals resistant to myeloablative doses of Taxol, and in vitro studies have shown that MDR-transduced human CD34+ cells can generate drug-resistant multipotential hemopoietic progenitors such as long term culture-initiating cells. Given these results, phase I clinical trials are currently under way to evaluate feasibility and treatment-related toxicity of MDR gene transfer in cancer patients by means of safe retroviral vectors. Finally, Taxol treatment of MDR transduced mice and human CD34+ cells have indicated that MDR is a dominant selectable marker in vitro and in vivo, and vectors carrying both MDR and non selectable genes such as beta-globin or glucocerebrosidase could be used in the next future for gene therapy of inherited disorders like thalassemia or Gaucher disease.
Centro Trasfusionale e di Immunologia dei Trapianti, Department of Hematology, Ospedale Maggiore Policlinico, Milano, Italy.
F
F
Bertolini
C
C
Corsini
L
L
Lazzari
D
D
Soligo
L
L
De Monte
M
M
Ward
A
A
Bank
G
G
Sirchia
D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D018432:Drug Resistance, Multiple / Q000235:genetics*; D018014:Gene Transfer Techniques; D006410:Hematopoiesis / Q000502:physiology*; D006801:Humans; D008722:Methods; D051379:Mice