Department of Cancer Biology
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo NY USA 14263
Email: harry.slocum@roswellpark.org

Harry K. Slocum, PhD, joined the faculty at Roswell Park Cancer Institute in 1976 in the Department of Experimental Therapeutics. He now works as a Cancer Research Scientist in the Department of Cancer Biology.

Dr. Slocum earned his doctorate in Biochemistry from the State University of New York at Buffalo (1974) and completed post-doctoral work in Molecular Immunology at the Scripps Clinic and Research Foundation, La Jolla, CA in 1976.

Dr. Slocum's research interests include understanding cell biology of cancer, cell interaction and growth control, cellular heterogeneity and the mechanism of cellular resistance to anticancer agents. He is a member of the American Association for Cancer Research and the American Society of Clinical Oncology.

Dr. Slocum has authored or co-authored more than 180 journal articles, abstracts and book chapters.  He has mentored over 90 students in his laboratory during his career at Roswell Park Cancer Institute. 

Program: Therapeutic Selectivity; Drug Resistance; Cell Cycle Control; Topoisomerase I agents and antimetabolites in combination
Therapeutic Selectivity, Drug Resistance, Cell Cycle Control: A major effort is being made to increase collaborative research with clinical departments at this Institute to enhance the design, implementation and validation of laboratory based clinical trials. This research includes 1) development of target-specific new drugs with greater therapeutic efficacy and selectivity; and 2) cell cycle genes as targets for chemotherapy.

Cellular responses are determined in novel in vitro assays, including those which determine responses of individual cells, and results are analyzed using new quantitative approaches to reveal the nature and intensity of drug interactions. Studies are conducted at the molecular level through determination and manipulation of gene expression. Of particular interest are those proteins involved in cell cycle control and apoptosis. Ideas generated by these studies are tested in vivo in unique animal models, and brought to clinical trial through collaborations. The findings of studies conducted this year are summarized below:

Description of Research

• Interleukin-15 protects against drug induced toxicities and potentiates antitumor activity of 5-fluorourical and irinotecan alone and in combination in rats bearing colorectal cancer.
• Persistent induction of apoptosis and suppression of mitosis are the bases for curative therapy with FU prodrugs in a colorectal tumor model.
• Alpha-fluoro-b -alanine modulates the antitumor activity and toxicity of 5-fluorouracil.
  A novel class of orally active highly lipophillic topoisomerase I inhibitors (karenitecins) has been developed; BNP1350 has undergone early preclinical studies and GLP toxicology in expectation of Phase I clinical trials.
• Cyclin E-Cdk2 activation is coupled to cell cycle arrest and inhibition of DNA replication induced by the thymidylate synthase inhibitor, raltitrexed.
• Overexpression of Bax laters the mechanism of drug-induced cell death in human head and neck carcinoma A253 cells. Cyclin D1-Cdk5 overexpression and MCM3 cleavage are involved in bax-associated spontaneous apoptosis and differentiation in a human head and neck carcinoma xenograft model (A253).
• Clinical chemosensitivity of head and neck squamous cell carcinoma (HNSCC) is related to high bax:bcl-2 protein expression ratio, but not to mutant p53.
  Development of a new semiparametric approach for the assessment of the combined-action of anticancer agents, and development of a new pharmacodynamic paradigm for modeling in vitro drug cytotoxicity and resistance.
• Novel cellular determinants have been defined for reversal of multidrug resistance in cells expressing p170-glycoprotein. Topotecan resistance can be reversed by a new dihydropyridine analogue, PAK-200S, in human ovarian and breast cancer cells that overexpress the p170-glycoprotein (pgp170).
• Therapeutic synergy between irinotecan and FU is based on recruitment of cells into S-phase by irinotecan (low doses), low level of endogenous hmLh1 and p73.

Students
Our primary interest is in drug response at the cellular level, and its role in determining the outcome of cancer chemotherapy. The emphasis is on the study of individual cells, particularly their proliferative behavior, the influence of anticancer agents on this behavior, and cellular characteristics which are associated with the ability to resist anticancer agents. Both cultured cells and cells of clinical specimens are of interest, and current techniques of cell and tissue culture, in situ analysis and digitized image analysis are being employed and developed.