Recently developed pharmaceutical manufacturing processes based on recombinant molecular biology and biotechnology methods present us with unresolved critical concerns related to the long-term effects of biotechnology-derived products. One concern is the issue of whether growth factors such as G-CSF, GM-CSF, M-CSF, IL-3, IL-1 and stem cell growth factor have any carcinogenic potential by themselves or more likely potentiate the carcinogenicity of other known drugs such as chemotherapeutic agents. Currently available in vitro data suggest this latter possibility may be a genuine concern. There has been no animal study conducted for the long-term safety assessment of the hemopoietic colony stimulating factors (CSFs). The main regulatory objective of this study is, therefore, to gather sufficient in vivo data for safety information in selecting what carcinogenic chemotherapeutic agents may be safely used with CSFs. Potential results from the proposed animal study are expected to provide relevant information for a more complete risk-benefit evaluation of a given combination of CSFs and chemotherapeutic agents. Hence, we designed 3 separate experimental approaches for the above objectives. One is to examine the potential modulation by colony stimulating factors on the carcinogenicity of a chemotherapy agent in mice. The second approach is to develop an in vivo murine long-term bone marrow stromal cell and stem culture using the xenotransplant methodology. With this long-term culturing system, one can examine the long-term effects of a chemotherapeutic agent. The third experimental approach is to evaluate the effects of CSFs on the mutagenic potential of a known mutagen using a recent recently developed transgenic mouse (Big Blue mouse). A control experiment using this short term in vivo mutagenic assay system is being carried out.
