Major Accomplishments

Pharmacokinetics and Pharmacogenetics of Irinotecan

The Analytical Component has been instrumental to the clinical development of irinotecan, a drug approved by the FDA in 2000 as first-line therapy for the treatment of patients with metastatic colorectal cancer in combination with 5-fluorouracil/leucovorin (5-FU/LV).

The lab began work with irinotecan in 1993, when it analyzed samples from a clinical trial and demonstrated a correlation between diarrhea and glucuronidation of SN-38, the active metabolite of irinotecan. Subsequent work identified UGT1A1 as one of the main enzymes catalyzing the formation of SN-38 glucuronide. Following this, the Core was involved in a pharmacogenetic study aiming to evaluate the association between the prevalence of severe toxicity and UGT1A1 genetic variation. This clinical trial was important in determining that genetic variants UGT1A1*28 (5-8 copies of a TA repeat) and -3156G>A in the promoter of the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.

Based on the study results, the irinotecan label has been revised to warn that homozygosity for UGT1A1*28 is a risk factor for severe neutropenia, and recommends that patients with this genotype should be treated with a reduced starting dose of irnotecan.

For more information: Pfizer's Camptosar: Irinotecan HCI Injection

Importance of DNA repair and inhibition by O 6-benzylguanine (O 6-BG)

The O 6-alkylguanine-DNA alkyltransferase (AGT) protein is responsible for repairing cytotoxic damage at the O 6-position of guanine in DNA introduced by DNA damaging chemotherapeutic agents (BCNU, temodar, DTIC, procarbazine). Thus, the presence of AGT in tumor cells confers resistance to these agents. Dr. Dolan contributed to the design of a low-molecular weight inactivator of the AGT repair protein, based on an understanding of the substrate specificity of the protein and the SN 2 bimolecular nature of the reaction. The Pharmacology Core facilities were instrumental in evaluating the pharmacokinetics, pharmacodynamics, and pharmacogenetics of BG. Investigators from Duke University, Johns Hopkins University, University of Cincinnati, and NCI sent samples for pharmacokinetic and/or pharmacodynamic analysis in adults and pediatric population in early phase clinical trials.