The Preclinical Pharmacology Core Laboratory provides laboratory support for the Drug Development Program of the Memorial Sloan-Kettering Cancer Center (MSKCC).
This facility conducts initial pharmacological, biochemical and toxicological investigations on new compounds with the potential anticancer activities, which are either synthetic chemicals or natural products. Priority is placed on evaluating the in-house new compounds synthesized in the BioOrganic Chemistry Laboratory headed by Samuel Danishefsky, PhD. and the Preparative Synthesis Facility. The aims are to perform the early discovery stage of evaluations for anticancer drugs, and to provide feedback for bio-activity-directed chemical synthesis. The work for in vitro structure-activity relationships are followed by the in vivo pharmacological evaluation such as anti-tumor efficacy in nude mice xenograft models, toxicology rodents and in dogs. Optimization of dosage, route and schedule of drug administration and formulation of new drugs are also essential parts of the drug development. Support for other research laboratories in MSKCC need to be prearranged with the Program Chairman, Dr. David Scheinberg, and the Facility Head with regard to the amount of work needed, time frame to complete the project, and the availability of budget.
The typical services provided by this core include:
In Vitro Studies
Physical characterization of new compounds such as solubility, stability and formulation.
In vitro testing for cytoxicity in drug sensitive and drug resistant tumor cell lines using XTT or SRB assays.
Dose-effect relationship parameters including computerized quantitation of potency, the shape, and statistics of dose-effect curves.
Determination uptake and membrane transport of drugs using oil-layer microfuge techniques.
Determination of DNA cleavage and super-coiled DNA relaxation for certain compounds.
Consulting for drug combination experimental design and computerized data analysis for experiments in vitro and in vivo.
Computerized quantitation of synergism, additive effect and antagonism as well as determination of combination index, dose-reduction index, isobologram and polygonogram.
Enzyme assays and enzyme kinetic analysis.
In Vivo Studies
For selected compounds, testing of antitumor efficacy in tumor bearing mice, xenograft nude mice or scid mice, with regard to the maximal tolerated dose, the proposed route of drug administration and the schedule of administration. Body weight, tumor volume or percent increase in life span in tumor bearing mice will be measured prior, during, and following the drug treatment.
Animal experiments in mice or rats for pharmacokinetic and metabolic studies will be carried our in the core. Analytical measurements of metabolites and pharmacokinetic parameter analysis will be conducted in the Pharmacology Analytical Laboratory headed by Dr. Nian Wu.
For selected compounds, toxicological studies will be carried on in mice or rats, with regard to the body weight changes, observations and recording of symptoms, and abnormalities or lethality. Blood samples will be forwarded to the Hematology Service and the Department of Clinical Chemistry, respectively, for hematologic and blood chemistry analysis.
Pathological and histopathological studies will be carried out in this core. However, sample preparations and examinations will be performed by the Animal Health Service, Research Animal Resource Center, or by the Pathology Service, Memorial Hospital.
