Magazine article Drug Topics

New Drug Development a Long, Arduous Process

Magazine article Drug Topics

New Drug Development a Long, Arduous Process

Article excerpt

It's been a long time--30 years--since taxol was first screened for possible anticancer activity by scientists in the preclinical New Drug Research Program at the National Cancer Institute.

But it wasn't until this year that 6,000 patients with breast, ovarian, and other types of cancer began to receive the taxol in phase III drug trials and on a compassion ate-use basis via a Cooperative Research and Development Agreement between NCI and Bristol-Myers Squibb. Taxol will finally be put to market in 1993.

Fortunately, most anticancer and anti-AIDS drugs don't take that long to move into clinical testing. The anti-AIDS drug dideoxycytidine, an antiviral pharmaceutical, became accessible to AIDS patients in a record 12 months.

Both drugs went through a similar developmental process. But the evolution of taxol was severely hobbled by difficulties in isolating it from the bark of yew trees that grow in the Pacific Northwest. Another 20 years elapsed before enough of the compound could be collected to put it through toxicology studies that would determine its viability as a clinical candidate.

Similarly, derivatives of the highly toxic compound camptothecin, expected to be effective in colon cancer, are emerging on the clinical horizon after 30 years of trial and error; the most recent is 9-amino camptothecin, which will go into clinical testing soon.

Under the aegis of NCI's New Drug Research Program, approximately 10,000 synthetic and plant-derived compounds are submitted by academic institutions, independent investigators, ad chemical and pharmaceutical companies for screening each year in the hope that there might be anti-AIDS and anti-cancer activity. Of that number, several hundred will be selected for testing in mice. Ten, maybe 20, will ultimately find their way into clinical trials.

"The NCI has hundreds of suppliers around the world--we very actively solicit new compounds," reported Saul A. Schepartz, deputy associate director of the NCI's Developmental Therapeutics Program.

In fact, the NCI will screen any compound that looks as if it will lead to clinically useful agents. They do this via human cell cultures based on anti-HIV screens and tumor cell lines from a variety of organs and tissues--spleen cells, liver cells, epidermal cells, lymph node cells. These compounds may be rationally designed chemical structures created to have specific effects. Or they might be previously unknown agents with an unpredictable outcome.

But that's only the beginning. If any of these potential drugs have significant anticancer activity and aren't too toxic--200 may fall into that category--they will be interested in mice that have been immune-deprived to stimulate growth of tumors.

"If an anticancer compound inhibits the growth of a tumor or brings about regression of an established tumor without killing the animal, we do an evaluation and make a decision as to whether the compound should be investigated further," noted Schepartz. Testing for potential anti-AIDS drugs, however, is still primarily confined to in vivo human cell lines in the absence of viable animal models in which direct simulations of the HIV virus can be duplicated.

Promising drug candidates are sent to outside research companies such as Research Triangle Institute in Research Triangle Park, N.C. There, analyses define a drug's physical and chemical characteristics in precise detail--a process that can take weeks or even months. …

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