days in breast cancer patients and 14, 17, 18, 18, 24, and 27 in 
advanced CML patients who have been transplanted with CD34 selected 
peripheral blood and marrow cells. The University of Denver has 
observed an average of 17 days to 500 neutrophils/cu mm in advanced 
breast cancer patients. 
As shown in Figure 1, our own laboratory has shown that introduction 
of the MDR-1 cDNA containing safety modified retrovirus into the 
marrow cells of BALB-C mice before transplant shows that the marrow 
cells of the mice transplanted with the MDR-1 modified marrow are 
more resistant to Taxol than are mice transplanted with unmodified 
marrow. 
The marrow become resistant to Taxol chemotherapy using transduction 
procedures which give integration of the virus into only 1-10% of the 
cells suggesting that in vivo selection of the MDR-1 modified cells 
occurs during chemotherapy. During the past two years, considerable 
progress has been made in the introduction of additional sequences 
into the somatic cells of patients in both constitutional as well as 
acquired molecular diseases (9-13) . This has been accomplished with 
a family of safety-modified retroviruses which have been modified so 
that they cannot replicate in the normal or abnormal somatic cells of 
the patients. The sequences required for viral replication have been 
removed from the viruses, and placed in fragments in different parts 
of the genome of "producer cell lines", in which the replication 
incompetent safety-modified viruses can occur. These viruses are not 
harmful so long as they are not contaminated with replication 
competent helper virus, or viruses which can combine with the safety- 
modified viruses in a way which preserves the functional MDR-1 
transgenome and restores (integrates) the rest of the replicating 
functions into the virus in an active array. 
Producer cell lines can support the proliferation and replication of 
safety-modified viruses. The producer cell lines contain the 
replicative function of the virus. The safety-modified viruses can be 
grown in these cell lines. The use of safety-modified viruses from the 
cell lines has not led to the appearance of replication competent 
virus over the past two years in 250 laboratories. In addition, the 
use of these retroviruses in patients has not led to any abnormal 
disease state, or toxicity in patients in whom these viruses have been 
used for therapy (15) . This data led to several therapeutic trials 
which involved the modification of the somatic cells of patients for 
genetic marking and for the replacement of missing or defective genes 
in a number of diseases. We have been involved in this work at M.D. 
Anderson, and have at the moment three protocols approved by the NIH 
Recombinant DNA Advisory Committee, and one protocol FDA-approved and 
ongoing at the M.D. Anderson Cancer Center at this time (16-19) . We 
have shown in our own laboratory that we can achieve transduction 
frequencies in the 1-5% range even with the normal hematopoietic 
progenitor cells (17) . Malcolm Brenner of St. Jude Children's 
Research Hospital has shown that these vectors, when used to modify 
the marrow of AML patients in remission, lead to a hematopoietic 
population following transplant which is positive for the retroviral 
transgenome at a frequency after transplant which equaled the 
Recombinant DNA Research, Volume 17 [665] 
