C. HESDORFFER 4/93 
2 . SPECIFIC AIMS : 
Intensive cancer chemotherapy usually requires concomitant 
autologous bone marrow transplantation (ABMT) because of the 
dose-limiting bone marrow toxicity of the chemotherapy used. 
This approach is especially useful for tumors not involving the 
bone marrow. In many cases, this marrow toxicity is due to the 
inadequate level of expression of the multiple drug resistance 
MDR1 (MDR) gene in normal bone marrow cells; MDR protein pumps 
certain drugs and other substances out of cells. The goal of 
this proposal is to use safe, defective retroviruses to transfer 
and express the MDR gene in the bone marrow cells of patients 
with advanced cancer undergoing ABMT who may subsequently be 
treated with drugs that require MDR for their inactivation (MDR- 
responsive drugs) commonly used in cancer chemotherapy; these 
include anthracyclines, vinca alkaloids, etoposides, and taxol. 
This strategy, if successful, should enrich the marrow for 
transduced MDR-expressing cells, and reduce bone marrow toxicity 
associated with subsequent exposure to these drugs. These 
studies may also result in safer and more feasible higher dose 
chemotherapy for patients with advanced cancer which may lead to 
longer survival and increased chances of cure for these patients. 
The specific aims of this protocol are; 1) To analyze the 
extent of transfer and expression of the MDR gene into the bone 
marrow cells of humans with advanced cancers; and 
2) To determine the toxicity of this treatment. In patients 
subsequently treated with taxol, an MDR-responsive drug, we will 
have the opportunity to evaluate if this treatment leads to 
enrichment for MDR-transduced and expressing bone marrow cells. 
This may lead to decreased marrow toxicity following taxol 
treatment . 
3 . BACKGROUND DATA AND SIGNIFICANCE : 
Successful HLA-compatible allogeneic bone marrow 
transplantation in humans is a major impetus for these studies 
(1-4). The availability and therapeutic advantage of autologous 
bone marrow transplantation (ABMT) (5-8) provides additional 
enthusiasm for this approach. The goal of the studies in this 
grant is to provide a new approach to avoid bone marrow toxicity 
in patients with cancer. To accomplish this, we plan to use the 
human MDR1 (MDR) gene to select bone marrow cells that contain 
and express this gene. Normal human bone marrow cells contain 
low levels of MDR, and, thus, are particularly susceptible to the 
toxicity induced by certain classes of drugs (MDR-responsive 
drugs) . The general scheme to accomplish this gene therapy and 
overcome the toxicity will be: 1) Removal of bone marrow cells 
Recombinant DNA Research, Volume 18 
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