A number of studies have demonstrated that many useful cancer chemotherapeutic compounds, and more experimental agents such as gamma interferon (IFNgamma), are potent and efficacious inducers of terminal differentiation in both myeloid leukemias and in some solid tumors. However, the biochemical mechanisms through which these agents induce maturation in tumor cells are not well understood. In the proposed studies, the role of membranegenerated signals in the induction of tumor cell differentiation by human recombinant IFNgamma will be investigated. Wildtype HL60 cells, TPAresistant sublines, and HL-60 cell clones selected on the basis of their resistence to the cylotoxic effects of IFNgamma, will be used to characterize the biochemical determinants of functional maturation in response to 1FNgamma. Preliminary studies have suggested that topoisomerase II, which has been widely implicated as a principal target of a number of useful anticancer drugs, may be an important component in the cellular response to inducers of differentiation. Combinations of specific chemotherapeutic agents which inhibit topoisomerase, such as m-AMSA or Adriamycin, and other drugs such as mitomycin C or cytosine arabinoside which are not effective inhibitors of this enzyme, will be evaluated on the basis of their impact on the ability of IFNgamma to induce leukemia laboratroy, have also demonstrated that IFNgamma is a potent inducer of differentiation in human colon adenocarcinoma cells. In parallel experiments, the biochemical mechanisms through which IFNgamma induces maturational responses will be investigated through the use of HCT116 colon tumor cell sublines which differ intrinsically in their degree of differentiation. The identification of drug combinations which preserve or possibly potentiate the activity of IFNgamma in these in vitro systems will be followed by studies on the terminal differentiation of murine leukemia cells in vivo, in mice treated by continuous infusions with recombinent murine IFNgamma, or IFNgamma in combination with other chemotherapeutic agents. the results of these studies to elucidate the biochemical determinants of the maturational activity of IFNgamma should provide a rational basis for the use of agents like IFNgamma in combination with other drugs in effective, differentiationdirected chemotherapies for leukemias and for solid tumors.
