OBJECTIVES 
1.1 To test the feasibility of introducing the MDR-l cDNA into normal 
hematopoietic early progenitor cells in advanced ovarian cancer 
patients through transduction of these cells with a safety- 
modified retrovirus which bears the MDR-l cDNA in a transcription 
unit. 
1.2 To determine the toxicity of modifying normal stem cells with MDR 
viruses on hematopoietic function following and during 
transplant. 
BACKGROUND 
Ovarian cancer strikes women in the prime of life. For those patients 
whose disease does not respond to regional approaches or conventional 
dose chemotherapeutic approaches to the control of the disease, an 80% 
mortality can be predicted. Furthermore, many of these patients 
exhibit signs of decreased marrow reserve at the time of attempted 
treatment of this residual disease, presumably due to the exposure of 
these patients to alkylating agents, irradiation, and other agents 
like Taxol, which on repetitive administration alone or in combination 
with other drugs, will result in a decrease in the rapidity of 
recovery following conventional dose chemotherapy. 
The response of ovarian cancer cells exhibits dose dependence, 
suggesting that the delivery of intensive doses of chemotherapy would 
alter the unfavorable natural history of this disease. This in vitro 
data, and the failure of conventional dose combination chemotherapy to 
alter the poor prognosis of patients whose disease does not respond to 
initial therapy, led to the testing of the efficacy of intensive dose 
combination chemotherapy (1) . Considerable interest in using intensive 
therapy supported by autologous transplants developed due to the fact 
that the marrow in ovarian cancer is almost never involved with cancer 
cells. The early trials with intensive therapy and autologous bone 
marrow transplantation did not lead to measurable increases in 
survival, although dramatic responses in terms of reductions in bulk 
disease were often seen (1-2). This suggested that the delivery of 
intensive but not ablative cyclical therapy following autologous bone 
marrow transplantation would lead to an improvement of survival. This 
expectation was based on the impressive responses of ovarian cancer 
cells to the intensive preparative regimens for autologous 
transplantation, and the persistence of small level disease during the 
post-transplant period. Unfortunately for these patients, the marrow 
graft is very fragile following transplantation such that it is not 
always feasible to deliver relatively intensive cyclical therapy 
following bone marrow transplantation. 
During the early 70' s, many investigators identified that epithelial 
neoplasms exhibited resistance to multiple drugs, and that if the 
cells were resistant to one member of this family of drugs, the tumor 
cells were often resistant to the other members of the family. Since 
the individual members of this family of drugs to which the tumor 
cells were cross resistant were not obviously related. Ling proposed 
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