The taxol supply crisis. New NCI policies for handling the large-scale production of novel natural product anticancer and anti-HIV agents.

Over the past 30 years, the National Cancer Institute has been involved in the preclinical and/or clinical evaluation of the majority of those agents approved for the treatment of cancer. Many of the new agents under consideration in the NCI program are either natural products or derivatives of natural product leads, and of critical importance to their development is the issue of drug supply. In responding to the drug supply crisis which emerged with the demonstration of the clinical efficacy of taxol, the NCI has identified several important lessons for those interested in natural product drug discovery and development. As a result, the NCI has developed plans to avert similar supply crisis in the future by initiating exploratory research projects for large-scale production of promising agents at the earliest possible point following the demonstration of confirmed antitumor activity. These plans, together with a review of the development of taxol, are presented in this paper.

Synthesis of congeners and prodrugs. 3. Water-soluble prodrugs of taxol with potent antitumor activity.

Taxol has shown good in vivo antitumor activity in a number of test systems. The formulation of taxol for antitumor testing has been difficult. Esterification at either C-2' or C-7 resulted in loss of in vitro tubulin assembly activity but not cytotoxicity. These observations suggested that esters at C-2' and/or C-7, which would tend to promote water solubility, might serve as useful prodrugs of taxol. The reaction of taxol with either succinic anhydride or glutaric anhydride in pyridine solution at room temperature gave the crystalline mono 2'-adducts 1b and 1f, respectively. Salts of these acids (1b, 1f, 1i) were formed by the addition of 1 equiv of the corresponding base, followed by evaporation and/or freeze-drying of the solvent(s). The salts had improved antitumor activity as compared to the free acids. The triethanolamine and N-methylglucamine salts showed greatly improved aqueous solubility and were more active than the sodium salts. The glutarate series was preferred because of the higher activity and the higher yields obtained. 2'-Glutaryltaxol (1f) was coupled with 3-(dimethylamino)-1-propylamine, using CDI, to form in excellent yield the amino amide 1o. The hydrochloride salt (1p) showed good solubility and was extremely potent and active. At 10 mg/kg, in the B16 screen, 1p gave a T/C of 352 with 5 out of 10 cures. In the MX-1 breast xenograft assay, this prodrug gave values of -100 at doses of 40 and 20 mg/kg, with all live animals being tumor free.

Plants as sources of antimalarial drugs: in vitro antimalarial activities of some quassinoids.

Fourteen quassinoids, obtained from simaroubaceous plants, were tested for in vitro antimalarial activity. All of these inhibited the incorporation of [3H]hypoxanthine into Plasmodium falciparum in vitro at concentrations below 0.41 microgram ml-1. The two most potent quassinoids, bruceantin and simalikalactone D, showed 50% inhibitory concentration values of 0.0008 and 0.0009 microgram ml-1, respectively. The results are compared with the antiamoebic, antileukemic, and cytotoxic activities of these compounds reported in the literature.

Didemnin B. The first marine compound entering clinical trials as an antineoplastic agent.

A new class of marine compounds, the didemnins, with potent antitumor activity has been identified. They share the novel structure of a cyclic depsipeptide. Among three structurally related compounds, didemnin B is by far the most potent in its in vitro cytotoxicity and in vivo antitumor activity (0.001 microgram/ml inhibits the growth of L1210 leukemia cells by 50%). It also demonstrates good antitumor activity against B16 melanoma and moderate activity against M5076 sarcoma and P388 leukemia. The compound also has good antiviral and potent immunosuppressive properties. Although the precise mechanism of action for the cytotoxicity remains unknown, the agent inhibits protein synthesis more than DNA synthesis and the inhibition of protein synthesis is closely correlated with inhibition of L1210 cell growth. Toxicology studies in CD2F1 mice, Fischer 344 rats and beagle dogs reveal that major target organs are the lymphatics, gastrointestinal tract, liver and kidney. Phase I trials are currently in progress under the auspices of the National Cancer Institute.

Stability of the in vivo P388 leukemia model in evaluation of antitumor activity of natural products.

The stability of the P388 mouse leukemia model over 15 years was examined. Eleven natural products and one synthetic compound (5-FU) tested repetitively under the same conditions of dose and schedule were associated with no significant change in their activity. The P388 model, used in conjunction with other in vivo and in vitro tumor models, continues to be of value in the anticancer drug screening process.

Bruceantin, a potent amoebicide from a plant, Brucea antidysenterica.

Bruceantin, purified from an Ethiopian plant used to treat dysentery, killed Entamoeba histolytica in vitro (IC50 [the concentration of drug which decreased the number of colonies to half that of controls] = 0.018 microgram/ml). Six related quassinoids of 17 tested were also amoebicidal. No relationship between quassinoid structure and amoebicidal activity was apparent.

New natural products under development at the National Cancer Institute.

Twenty-six new agents of natural products origin which are under preclinical development as potential antitumor agents at the National Cancer Institute are discussed with reference to their sources, structures, antitumor activity, current status, and future potential as clinically effective drugs.

The National Cancer Institute's Natural Products Antineoplastic Development Program.

The present Natural Products Antineoplastic Development Program of the National Cancer Institute is reviewed, and the potential new anticancer agents being developed in each of the three natural products programs, fermentation, plant, and animal, are discussed [2, 5].

New natural products of interest under development at the National Cancer Institute.

Fourteen new agents of natural products origin which are under development as antitumor agents at the National Cancer Institute are discussed with reference to their sources, structures, antitumor activity, current status, and future prospects as clinically effective agents.