Sherry S. Ansher

Role of N-methyltransferases in the neurotoxicity associated with the metabolites of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other 4-substituted pyridines present in the environment

Amine N-methyltransferases in the brains of humans, monkeys, mice, rabbits and rats, as well as two homogeneous enzymes isolated from rabbit liver, are capable of N-methylating 4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenyltetrahydropyridine (MPTP), and 4-phenylpyridine to 1-methyl-4-phenylpyridinium ion (MPP+). The product in each instance is a neurotoxin. The suggestion is offered that the known long half-life of methylpyridinium compounds in brain may be due to limitations in transport of such charged metabolites out of this tissue and to metabolic recycling of the desmethyl species by amine N-methyltransferases. The methylation of pyridines to quaternary amines is suggested as a means by which lipophilic compounds, having gained entrance to the cell, are converted to charged species that efflux much less readily.

Implementation of Timeline Reforms Speeds Initiation of National Cancer Institute–Sponsored Trials

BACKGROUND The National Cancer Institute (NCI) organized the Operational Efficiency Working Group in 2008 to develop recommendations for improving the speed with which NCI-sponsored clinical trials move from the idea stage to a protocol open to patient enrollment. METHODS Given the many stakeholders involved, the Operational Efficiency Working Group advised a multifaceted approach to mobilize the entire research community to improve their business processes. New staff positions to monitor progress, protocol-tracking Web sites, and strategically planned conference calls were implemented. NCI staff and clinical teams at Cooperative Groups and Cancer Centers strived to achieve new target timelines but, most important, agreed to abide by absolute deadlines. For phase I-II studies and phase III studies, the target timelines are 7 months and 10 months, whereas the absolute deadlines were set at 18 and 24 months, respectively. Trials not activated by the absolute deadline are automatically disapproved. RESULTS The initial experience is encouraging and indicates a reduction in development times for phase I-II studies from the historical median of 541 days to a median of 442 days, an 18.3% decrease. The experience with phase III studies to date, although more limited (n = 25), demonstrates a 45.7% decrease in median days. CONCLUSIONS Based upon this progress, the NCI and the investigator community have agreed to reduce the absolute deadlines to 15 and 18 months for phase I-II and III trials, respectively. Emphasis on initiating trials rapidly is likely to help reduce the time it takes for clinical trial results to reach patients in need of new treatments.

The Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute

Abstract: The mission of the Cancer Therapy Evaluation Program (CTEP), a clinical research program of the National Cancer Institute (NCI), is to reduce the burden of cancer. CTEP plans, reviews, and coordinates clinical trials for investigational anticancer agents, from the inception of protocols through the preparation and submission of Investigational New Drug Applications (INDs) to the Food and Drug Administration (FDA). CTEP also serves as a liaison to the FDA for the extramural clinical research community and industry collaborators. Other CTEP functions include managing, tracking, and reviewing clinical protocols as well as monitoring, planning, and maintaining regulatory compliance of the clinical trials. In addition, CTEP coordinates the distribution of the investigational agents from industry collaborators for use in all NCI‐sponsored clinical trials. The advantages of collaborating with CTEP are described as well as details about the contractual framework, either a Clinical Trials Agreement (CTA) or a Cooperative Research and Development Agreement (CRADA), for such a collaboration. Many of the concerns raised by industry collaborators with respect to intellectual property, data access, and publications are also addressed.

The ability of amine N‐methyltransferases from rabbit liver to N‐methylate azaheterocycles

The substrate specificity of two homogeneous amine N‐methyltransferases from rabbit liver has been demonstrated to extend to the azaheterocycles pyridine, R‐(+)‐nicotine and S‐(−)‐nicotine. Both enzymes methylate R‐(+)‐nicotine at the pyridyl nitrogen to afford the N‐methylnicotinium salt, whereas S‐(−)‐nicotine does not act as a substrate for either enzyme. Surprisingly, R‐(+)‐nicotine is methylated at either the pyridyl nitrogen, or the pyrrolidine nitrogen, to afford the two isomeric monomethylate nicotinium ions when an enzymic preparation containing both methyl transferase activities was used. Under similar conditions S‐(−)‐nicotine was methylated only at the pyridyl nitrogen. The production of charged metabolites in‐vivo, from the large number of pyridine‐compounds that are used as drugs, or are present in the environment, may be of toxicological significance, in view of the reported toxicities of several such quaternary ammonium compounds.

National Cancer Institute Formulary: A Public‐Private Partnership Providing Investigators Access to Investigational Anticancer Agents

As part of the White House Cancer Moonshot Initiative, the National Cancer Institute (NCI) has developed a drug formulary to provide investigational anticancer agents to the extramural research community. This article describes how the NCI Formulary functions, how researchers may apply for access to drugs in the formulary, and the NCIs initial goals for formulary participation. Approved investigators may apply for access to formulary agents at: https://nciformulary.cancer.gov.