Stephen Bloom, College of Veterinary Medicine

With the chick embryo system, we were able to effectively address a long-standing question concerning the mechanism of selective lymphoid toxicity of the chemotherapeutic drug cyclosphosphamide. We showed for the first time that cylophosphamide (CP) selective toxicity towards the B-lineage lymphocytes, compared to T-lineage lymphocytes, was due to the actions of the phosphoramide mustard metabolite of CP inducing DNA cross-links and involving the downstream, rapid induction of apoptosis in B-lymphoctyes. This work stimulated new studies to determine the mechanisms of drug-induced selective toxicity in cancer cells, especially lymphomas treated with CP and other drugs.

A major reason for failure to cure lymphoma and other cancers is cellular drug resistance. Mechanisms of drug resistance have been elusive and can be masked by such mechanisms as the drug efflux pump. This difficulty has been overcome with the development and use of avian virally-transformed lymphoma cell lines in which the drug efflux pump has the same activity in drug resistant and sensitive cell lines. We have also shown that the amount of initial cellular damage induced by several drugs is similar in these cell lines. However, the downstream effects of drug exposure differ with the T-lineage lymphoma cells showing resistance to both cell cycle inhibition and apoptosis. The B-lymphoma cells are inhibited in S and G2 phases of the cell cycle and enter apoptosis rapidly and extensively.

We are presently studying the molecular mechanisms that regulate the differential cell cycle inhibition and apoptosis induction. The focus of this work is on expression of genes that regulate cell death and particular processes in the apoptosis cascade such as mitochondrial dysfunction, caspase activation, and endonuclease activation. We expect this research to contribute to the identification of molecular targets for new drug design.