C. HESDORFFER 4/93 
1. BACKGROUND MATERIAL : 
A. SUMMARY : 
Intensive cancer chemotherapy usually requires 
autologous bone marrow transplantation (ABMT) because of the 
dose-limiting toxicity to bone marrow cells of the chemotherapy 
used. This approach is especially useful for tumors not 
involving the bone marrow. In many cases, the toxicity is due to 
the low levels of expression of the human multiple drug 
resistance (MDR1) gene in human bone marrow cells. The goal of 
this proposal is to transfer and express the human MDRI (MDR) 
gene in human bone marrow cells of patients with solid tumors not 
involving the bone marrow who undergo ABMT in association with 
high-dose chemotherapy; this procedure should protect the marrow 
from bone marrow toxicity on subsequent administration of MDR- 
responsive anti-cancer drugs (anthracyclines , vinca alkaloids, 
etoposides, and taxol) . We have demonstrated efficient and 
stable transfer of the human MDR gene into mouse bone marrow stem 
cells, and a concomitant marked increase in expression of MDR in 
these cells. In addition, we have shown that enrichment of the 
population of MDR-expressing cells occurs on treatment of these 
live mice with taxol. We have also shown that human bone marrow 
precursor ( (CD34+) cells can be transduced with the human MDR 
gene and increase their expression of MDR after gene transfer. 
All these studies have been performed with supernatants from a 
safe and efficient MDR retroviral producer line developed in our 
laboratory . 
In this proposal, we present a protocol for the use of human MDR 
gene transfer into the bone marrow cells of patients undergoing 
ABMT in association with chemotherapy for advanced cancers. This 
protocol has two goals: 1) To analyze the extent of transfer 
and expression of the human MDR gene into the bone marrow cells 
of humans; and 2) To determine the toxicity of this treatment. 
In patients on this protocol who are subsequently treated with 
taxol, an MDR-responsive drug, we will also obtain information 
about whether increased MDR expression leads to enrichment for 
MDR-transduced bone marrow cells. This induction of high MDR 
expression, if “successful , may lead to decreased toxicity to the 
bone marrow when patients are subsequently treated with MDR- 
responsive drugs. If successful, this strategy may also permit 
significant increases in the dose intensity of drugs useful in 
advanced cancer such as taxol and adriamycin, and lead to longer 
survival of patients and the possibility of cure. 
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Recombinant DNA Research, Volume 18 
