In vitro anticancer screening of South African plants.

AIM OF THE STUDY: The purpose of the present study is to evaluate South African plants for their anticancer activity. MATERIALS AND METHODS: Plant species were collected throughout South Africa and voucher specimens were deposited and identified at the South African National Biodiversity Institute. Plant extracts were prepared and screened for in vitro anticancer activity against a panel of three human cell lines (breast MCF7, renal TK10 and melanoma UACC62) at the CSIR. Plant extracts that exhibited anticancer activity against these three human cell lines were screened by the NCI against sixty human cancer cell lines organized into sub-panels representing leukaemia, melanoma, cancer of the lung, colon, kidney, ovary, central nervous system, breast and prostate. RESULTS: A total of 7500 plant extracts were screened for in vitro anticancer activity against breast MCF7, renal TK10 and melanoma UACC62 human cell lines between the period 1999 and 2006. Hits were classified into four categories based on their total growth inhibition of the cell lines. A hit rate of 5.9% was obtained for extracts which showed moderate activity and these were screened by the NCI against a panel of sixty human cancer cell lines. The extracts of plant species with limited published information for their anticancer properties were subjected to bioassay-guided fractionation and the active constituents isolated and identified. The largest number of plant specimens in this study was from the family Asteraceae, which is rich in sesquiterpene lactones. CONCLUSIONS: Although the extracts of the plants were randomly selected, 68% of these plant species which were hits in the screening programme are reported to be used medicinally. Based on our data, it appears that unrelated medicinal use of the source plants may serve as an initial guide to selection of plants for anticancer screening.

Natural products from marine invertebrates and microbes as modulators of antitumor targets.

Over the last twenty-five to thirty years, exploration of the marine fauna and microbial flora has progressed from a random search by natural product chemists who liked to dive and wished to combine their hobby with their profession, to fully integrated programs of systemic investigation of the chemical agents elaborated by marine organisms of all phyla (as presumably defensive agents against predators) for their potential as leads to human-use drug candidates where the putative mechanisms have been identified as modulation of, and/or interaction with, potential molecular targets, rather than just exhibiting general cytotoxicity. This review is not exhaustive but is meant to cover the highlights of such agents and is arranged on a (nominal) target basis rather than by organism or chemical class.

Anticancer drug discovery and development throughout the world.

This year's American Society of Clinical Oncology International Symposium devoted 2 hours to a lively discussion of various aspects of anticancer drug discovery and development throughout the world. The scientific program started with an overview of efforts directed toward promoting international collaboration in natural product-derived anticancer drug discovery. This was followed by a discussion on the importance of interethnic differences and pharmacogenetics in anticancer drug development. Thereafter, this part of the program was completed by a description of the activities of the newly created Singapore-Hong Kong-Australia Drug Development Consortium and an overview of the contribution of Japan to anticancer drug development. The logistics and regulatory aspects of clinical trials with new anticancer agents in different parts of the world were then presented, with an emphasis on Europe, North America, and Japan. The program was completed with a panel discussion of the efforts to harmonize the exchange of clinical data originating from one region of the globe with other territories, with input from official representatives of the United States Food and Drug Administration and the Medical Devices Evaluation Center of Japan.

Natural product-based anti-HIV drug discovery and development facilitated by the NCI developmental therapeutics program.

During the decade 1987-1996, the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) provided infrastructure support for both intramural and extramural anti-HIV (human immunodeficiency virus) drug discovery research and development. This retrospective review describes some of the anti-HIV lead discovery and development that took place under DTP auspices or which was substantially facilitated by resources made available through the DTP. Examples highlighted include leads identified through the initial screening of pure natural product derived compounds and those derived from bioassay-guided fractionation of crude natural product extracts, and these are classified according to the mechanism of action targeting the critical steps within the replication cycle of HIV.

Medicinals for the millennia: the historical record.

Nature has been a source of medicinal agents for thousands of years, and an impressive number of modern drugs have been isolated from natural sources, many based on their use in traditional medicine. The use of herbal drugs is once more escalating in the form of complementary and alternative medicine. The past century, however, has seen an increasing role played by microorganisms in the production of the antibiotics and other drugs for the treatment of some serious diseases. With less than 1% of the microbial world currently known, advances in procedures for microbial cultivation and the extraction of nucleic acids from environmental samples from soil and marine habitats, and from symbiotic and endophytic microbes associated with terrestrial and marine macro-organisms, will provide access to a vast untapped reservoir of genetic and metabolic diversity. By use of combinatorial chemical and biosynthetic technology, novel natural product leads will be optimized on the basis of their biological activities to yield effective chemotherapeutic and other bioactive agents.

Natural product drug discovery in the next millennium.

Nature has been a source of medicinal agents for thousands of years, and an impressive number of modern drugs have been isolated from natural sources, many based on their use in traditional medicine. In the past century, however, an increasing role has been played by microorganisms in the production of antibiotics and other drugs for the treatment of some serious diseases. Advances in the description of the human genome, as well as the genomes of pathogenic microbes and parasites, is permitting the determination of the structures of many proteins associated with disease processes. With the development of new molecular targets based on these proteins, there is an increasing demand for novel molecular diversity for screening. Natural products will play a crucial role in meeting this demand through the continued investigation of world's biodiversity, much of which remains unexplored. With less than 1% of the microbial world currently known, advances in procedures for microbial cultivation and the extraction of nucleic acids from environmental samples from soil and marine habitats, will provide access to a vast untapped reservoir of genetic and metabolic diversity. The same holds true for nucleic acids isolated from symbiotic and endophytic microbes associated with terrestrial and marine macroorganisms. By use of combinatorial chemical and biosynthetic technology, novel natural product leads will be optimized on the basis of their biological activities to yield effective chemotherapeutic and other bioactive agents. The investigation of these resources requires multi-disciplinary, national, and international collaboration in the discovery and development process.

Antineoplastic agents from natural sources: achievements and future directions.

The influence of natural products upon anticancer drug discovery and design cannot be overestimated. Approximately 60% of all drugs now in clinical trials for the multiplicity of cancers are either natural products, compounds derived from natural products, contain pharmacophores derived from active natural products or are 'old drugs in new clothes', where (modified) natural products are attached to targeting systems. This review covers those materials that the authors are aware of as being in clinical trials through early 2000 and demonstrates how, even today, in the presence of massive numbers of agents from combinatorial libraries, the compounds produced by 'Mother Nature' are still in the forefront of cancer chemotherapeutics as sources of active chemotypes.

Isolation and structures of schleicherastatins 1-7 and schleicheols 1 and 2 from the teak forest medicinal tree Schleichera oleosa.

Bioassay (P-388 lymphocytic leukemia cell line)-guided separation of an extract prepared from the bark and stem of the Sri Lankan tree Schleichera oleosa led to the isolation of seven cancer cell growth inhibitory hydroxylated sterols designated schleicherastatins 1-7 (1-7) and two related sterols, schleicheols 1 and 2 (8, 9). The structure of schleicherastatin 1 (1) was completely elucidated by X-ray crystal structure determination. Based upon that defined structure, the remaining new sterol structures were deduced by highfield (300 and 500 MHz) NMR and MS interpretations. In this new series of sterols, hydroxylation at C-22 appears to be important for promoting cancer cell growth inhibition.

Discovery and development of antineoplastic agents from natural sources.

Nature has provided many effective anticancer agents in current use, such as the microbially derived drugs; dactinomycin; bleomycin and doxorubicin; and the plant-derived drugs, vinblastine, irinotecan, topotecan, etoposide, and paclitaxel. The search for novel antitumor agents from natural sources continues through collaboration among scientists worldwide in the investigation of coral reefs, rainforests, and deep subsurface thermal vents for novel bioactive compounds. The potential for drug discovery is being further enhanced by recent advances in procedures for microbial cultivation and the extraction of nucleic acids from environmental samples, resulting in the identification of novel microbes that provide a vast untapped reservoir of genetic and metabolic diversity. Manipulation of the biosynthetic pathways of microbial polyketides through genetic engineering permits the biosynthesis of bioactive polyketides not generated naturally.

Pyranocoumarins from tropical species of the genus Calophyllum: a chemotaxonomic study of extracts in the National Cancer Institute collection.

(+)-Calanolide A, a novel dipyranocoumarin from the Malesian tree Calophyllum lanigerum var. austrocoriaceum, and a closely related compound, (-)-calanolide B, isolated from Calophyllum teysmannii var. inophylloide, are representatives of a distinct class of nonnucleoside HIV-1 specific reverse-transcriptase inhibitor under development as an AIDS chemotherapeutic. NCI repository specimens totalling 315 organic extracts from 31 taxa of Calophyllum were analyzed for related pyranocoumarins using a simple TLC system. A total of 127 extracts was initially classified as "positive"; eight out of the 31 taxa examined, representing perhaps 28 species already described (1/7-1/8 of all the species in this genus), contained prenylated coumarins, suggesting that these compounds, while sometimes abundantly present, are not widespread in the genus. Representative members of the TLC-positive extracts were partitioned between CH2C12 and 25% aqueous MeOH; the CH2C12-soluble materials were then analyzed by TLC and 1H NMR to confirm the presence of pyranocoumarins. The anti-HIV activity of the partitioned extracts are also presented. This study suggested that there are several distinctive coumarin chemotaxonomic markers distinguishing species of this genus.

Paclitaxel (Taxol): a success story with valuable lessons for natural product drug discovery and development.

The discovery and development of paclitaxel, which covered a time span of some 30 years, has provided some important lessons for those involved in natural product drug discovery and development. These include the adoption of novel screens as they become available, the elucidation of mechanisms of action, and addressing the supply issue at an early stage of development. These issues, as applied to paclitaxel, are illustrated. The development of the NCI human cancer cell line screen, and its application to mechanistic studies through use of COMPARE analyses, are discussed, as is the production of the marine-derived anticancer agent, bryostatin 1, which provides another illustration of a successful approach to solving a supply issue. The history of the development of paclitaxel also illustrates the importance of multidisciplinary collaboration, and the various mechanisms used by the NCI Developmental Therapeutics Program for promoting such collaboration are presented.

Coral reefs, forests, and thermal vents: the worldwide exploration of nature for novel antitumor agents.

Nature has been a source of medicinal treatments for thousands of years, and plant-based systems continue to play an essential role in the primary health care of 80% of the world's population. Nature has provided many of the effective anticancer agents in current use, such as the microbially derived drugs, dactinomycin, bleomycin, and doxorubicin, and the plant-derived drugs vinblastine, irinotecan, topotecan, etoposide, and paclitaxel. The search for novel antitumor agents from natural sources continues with botanists, marine biologists, and microbiologists teaming up with chemists, pharmacologists, toxicologists, and clinicians in the investigation of coral reefs, rainforests, and deep subsurface thermal vents for novel bioactive compounds. The wealth of anticancer drugs of natural origin and critical aspects of the ongoing discovery and development process are discussed.

Natural product drug discovery and development: new perspectives on international collaboration.

Until recently, the prevailing attitude in developed nations regarded the world's genetic resources, which are mainly concentrated in the developing world, as a common resource of humankind, to be exploited freely irrespective of national origin. With the devastation being wreaked in the tropical rainforests and the resurgence in interest in recent years in the discovery of novel drugs from natural sources, particularly plants and marine organisms, the international scientific community has realized that the conservation of these global genetic resources and the indigenous knowledge associated with their use are of primary importance if their potential is to be fully explored. With this realization has come a recognition that these goals must be achieved through collaboration with, and fair and equitable compensation of, the scientists and communities of the genetically rich source countries. The signing of the United Nations Convention on Biological Diversity by nearly all of the World's nations has emphasized the need for the implementation of such policies. In this review, the articles of the Convention of relevance to the activities and practices of the natural products scientific community are briefly discussed. This discussion is followed by a summary of policies for international collaboration and compensation being implemented by several developed country organizations, and the perspectives on the current developments given by representatives of some of the source countries located in the regions of greatest biodiversity.

Cucurbitacins: differential cytotoxicity, dereplication and first isolation from Gonystylus keithii.

A characteristic pattern of differential cytotoxicity of extracts of Iberis amara seeds, predominantly toward renal tumor, brain tumor, and melanoma cell lines in the NCI human disease-oriented tumor screening panel, was traced to cucurbitacins E [1] and I [2]. This same differential cytotoxicity profile was detected in extracts of Begonia plebeja and Gonystylus keithii. Computer-assisted recognition of these profiles was followed by a rapid chemical fractionation, thus permitting the efficient dereplication of those extracts containing cucurbitacins B [3] and D [4], respectively. This is the first report of cucurbitacins from the genus Gonystylus.

Anti-HIV michellamines from Ancistrocladus korupensis.

Here we report details of the isolation and determination of the absolute configurations and comparative anti-HIV activities of novel, atropisomeric naphthylisoquinoline alkaloid dimers, michellamines A, B, and C, from a newly described species of Ancistrocladus from the Korup rainforest of Cameroon. We further provide a more extensive analysis of the range of anti-HIV activity of michellamine B, the most potent and abundant member of the series. Michellamine B inhibited HIV-induced cell killing and viral replication in a variety of human cell lines, as well as in cultures of human peripheral blood leukocytes and monocytes. Michellamine B was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6 and the pyridinone-resistant strain A17; the compound also inhibited several strains of HIV-2.

Ethnobotany and drug discovery: the experience of the US National Cancer Institute.

Between 1960 and 1981 the National Cancer Institute (NCI) screened 114,000 extracts of 35,000 plants, mainly collected in temperate regions. Of the three clinically active anticancer drugs so far discovered in that programme, none was isolated from a plant collected on an ethnobotanical basis, though various Taxus species, which are the source of taxol, are reported to have been used medicinally. Since 1986, the NCI has focused its collections in tropical and subtropical regions worldwide; collections cover a broad taxonomic range, though priority is given to medicinal plants when relevant information is available. As of August 1993, 21,881 extracts derived from over 10,500 samples had been tested in a screen for activity against the human immunodeficiency virus (HIV); 2320 of these extracts were of medicinal plant origin. Approximately 18% of both the total number of extracts and the medicinal plant-derived extracts showed significant anti-HIV activity; in each instance about 90% of the active extracts were aqueous. The activity of the aqueous extracts has been attributed mainly to the presence of polysaccharides or tannins. Four plant-derived compounds are in preclinical development at the NCI; only one of the four sources plants, obtained from a noncontract source, was collected on an ethnobotanical basis. At this stage the results indicate that the current NCI collection policy offers the best chances for the discovery and development of agents for the treatment of AIDS (acquired immune deficiency syndrome) and cancer.

Two new cytotoxic chalcones from Calythropsis aurea.

The crude extract of Calythropsis aurea (Myrtaceae) produced a pattern of differential cytotoxicity in the NCI 60 cell line assay which was similar to those of known tubulin-interactive compounds. Cytotoxicity-guided fractionation led to the isolation of two new chalcones, calythropsin [1] and dihydrocalythropsin [2], which were responsible for the activity. Calythropsin was demonstrated to have a weak effect on mitosis, and presumably also on tubulin polymerization.