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 four protocols approved by the NIH 
Recombinant DNA Advisory Committee, and two protocols 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 frequency of the 
marrow cells following in vitro exposure to the MDR viruses before 
transplant. We have similar data in CML patients, a report of which is 
in press in Blood (see Appendix C) . These studies have also shown that 
the retroviruses is functional by the criterion of resistance to the 
bacterial resistance gene Neo. The presence of the retroviral 
transgenome in the cells has persisted up to greater than 1-1/2 years. 
Figure lA 
Myelosuppression in Control Mice and MDR Transduced 
Mice After Taxol Chemotherapy - 20 mg/kg 
[Recombinant DNA Research, Volume 19 
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