OBJECTIVES 
1.1 To test the feasibility of introducing the MDR-1 cDNA into normal 
hematopoietic early progenitor cells in advanced breast cancer 
patients through transduction of these cells with a safety- 
modified retrovirus which bears the MDR-1 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 
Breast 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. 
The poor response of advanced breast cancer led to the testing of the 
efficacy of intensive dose combination chemotherapy (1). Methods of 
separating normal cells and breast cancer cells and detecting the 
presence of 1 cancer cell in 10,000 normal cells (see Appendix G) . The 
early trials with intensive therapy and autologous bone marrow 
transplantation of breast cancer 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. 
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. Work designed 
to isolate this efflux pump protein culminated in the isolation of the 
pl70 glycoprotein and the MDR-1 cDNA and gene. 
Subsequent laboratory work on tumor cell lines which exhibited 
resistance to these drugs, or on tumor cell lines into which the cDNA 
for the MDR- 1 cDNA was introduced by transduction, led to the 
conclusion that the MDR-1 cDNA conferred resistance to the following 
drugs: actinomycin D, VP-16, Velban, vincristine, adriamycin, and 
Taxol. In addition, exposure of the cells of patients leads to 
increases in the levels of the MDR-1 mRNA and in the protein GP170 for 
which it is the coding sequence. 
Studies of patients with breast cancer have shown that the elevation or 
even the presence of detectable levels of the MDR-1 mRNA or protein in 
breast cancer cells is very uncommon (3-5) , and that even after 
exposure to the MDR-1 drugs, that the levels of elevated MDR-1 (which 
are 2 to 3-fold higher than those which are detectable before 
treatment) , are at least 3-fold lower than the levels which are 
achievable in hematopoietic stem cells which have been transfected with 
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