AIDS Research at the NIH: A Critical Review

Drug Discovery + Preclinical Development. NCI spent $42.5 million on drug discovery and preclinical
development in 1991, one fourth of its AIDS effort. $24.8M was spent extramurally, and $16M intramurally.
Michael Grever MD, the acting director of the Developmental Therapeutics Branch of the Division of Cancer
Treatment (DCT) supervises this effort, the bulk of which is directed at identifying and developing
treatments for HIV itself and the AIDS related malignancies, Kaposi's sarcoma in particular. NCI's
Developmental Therapeutics Program (DTP) procures, solicits and screens compounds for activity against
acutely HIV infected T cell lines. The original assay was developed by Hiroaki Mitsuya in Broder's group,
which brought the world the dideoxynucleosides. This screen was standardized and scaled up by 1987
for an intramural, high-volume AIDS drug screen in the Antiviral Evaluations Branch. AEB's chief, John
Bader, PhD, heads this project, which has now screened 47,600 agents (23,500 synthetic compounds and
24,100 natural product extracts) since its inception. 416 (or 0.8%) of these showed selective anti-HIV
activity, but fewer than 1% of these will go on to clinical development. Supplementing its in-house screen,
NCIl farms some work out to extramural contractors and grantees. Some compounds are tracked down
through computer databases, and if they are not commercially available, NCI can have them synthesized
or purified from natural sources. NCI supports synthetic chemistry to develop new nucleoside and folate
analogues, and congeners and prodrugs of lead compounds identified by screening.
NCI's Natural Products Program (NPP) contracts out plant collection in Central and South America, Africa
and Southeast Asia; and supports harvesting of marine microorganisms from the world's oceans. Extracts
of novel plant or microbial species are then tested for activity against HIV in NCI's intramural screen or by
extramural grantees. Intramural researchers are also testing Chinese medicinal herbs for anti-HIV activity,
and synthesizing less toxic single-chain ribosome inactivating proteins (SCRIPs) derived from trichosanthin
and other plants. The NPP has prioritized four compounds for development: Bryostatin, an anti-cancer
agent which might be useful in treating AIDS lymphomas; Prostratin, a phorbol ester which might protect
cells from the damaging effects of HIV; Sulfollpid, a compound with anti-HIV activity; and Camptothecin,
a potent anti-tumor compound, which also inhibits HIV topoisomerase I. The NPP identified six new
classes of tropical plant-derived compounds which are active against HIV.
NCI also supports so-called "rational drug design" approaches to anti-HIV therapy, using structure-activity
relationships to devise inhibitors of viral proteins and enzymes or host receptors, proteins and transcription
factors. NCI is also focusing on the cell cycle and its division in order to develop new cancer drugs. Much
of this work occurs at the AIDS Basic Research Program at the Frederick Cancer Research Facility.
Compounds which pass the NCI anti-HIV screen with flying colors (and which don't do so by killing the cell
line used) are sent on to preclinical development programs administered by the Laboratory of Drug
Discovery, Research and Development (LDDRD), which studies the agent's toxicology, animal
pharmacology, formulation and mechanism of action. NCI has contracts to scale up production of the
compound if necessary. Several labs in the Division of Cancer Treatment (DCT) also perform preclinical
evaluations of candidate agents. NCI highlighted four drugs for high-priority preclinical development in FY
1993: Fluorodideoxycytidine (F-ddC), a ddC derivative which may cause less neuropathy than its parent
compound [flush away your troubles with fluorine!]; Oxathilln carboxanilide, which inhibits HIV binding to
the CD4+ cell surface; SP-PG and TMP-2, two angiogenesis inhibitors
Immune-based Therapies are also part of NCI's AIDS program. Intramural investigators are working
cytokines and other biological response modifiers (BRMs). The Laboratory of Experimental Immunology,
in the Biological Response Modifiers Program (BRMP), in the Division of Cancer Treatment (DCT), has
been investigating the effects of cytokines on blood progenitor cells, the effects of flavone acetic acid on
cytokine expression, and the cytotoxic mechanisms of natural killer (NK) cells and cytotoxic T-lymphocytes
and methods to enhance the activity of these cell populations. Immunotoxins - conjugates of Pseudomonas
exotoxin + TGF-alpha, IL-2, IL-4, IL-6, IGF-1, acidic FGF, CD4, anti-Tac(Fv), or antitransferrin(Fv), are in
development for the treatment of cancers and HIV infection. NCl researchers are developing assays to
quantitate the production of cytokines in HIV infection. Of particular interest, is the institute's development

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