Cancer antitumor alkaloids

The metabolism of any drug is invariably of theoretical and practical importance, and the metabolic behavior of the ellipticine family of antitumor alkaloids and synthetic derivatives is no exception. A number of new developments have been described since the Suffness and Cordell review 10). The pharmacokinetics of elliptinium (5) have been studied in a human brain tumor clonogenic cell assay (250) and in metastatic breast cancer patients (257). In the latter study, the drug was mainly excreted in the feces ( C-labeled 5)... 

Preliminary observation on 16 cancer patients who have been treated with the above-mentioned total alkaloid preparation indicates that symptoms are improved. Thus hepatic cancer patients have claimed disappearance of pain, improvement of appetite, and reduction of ascites patients suffering esophageal cancer claimed to have the self-feeling of relaxation of pain and disappearance of vomiting and upset stomach as well as the improvement of appetite. These preliminary results are quite encouraging, but certainly more extensive investigations are needed before the antitumor action of the Gelsemium alkaloids can be established. 

Pharmacological activity has been studied for about 40 T. alkaloids. Some of these have been studied during a plant antitumor screening program carried out under the auspices of the National Cancer Institute of the U.S. National Institute... 

The isolation of the antitumor agents vincaleukoblastine (1) and leuro-cristine (2) from Catharanthus roseus (L.) G. Don has proved to be one of the most important developments in both natural product chemistry and the clinical treatment of cancer during the 1960s to 1980s. More alkaloids (over 90) have been isolated from C. roseus than from any other plant, and because of the complexity of the alkaloid mixture this work has required the most advanced isolation and structure determination techniques. The exceptional interest in the broad spectrum of antitumor activity of these compounds has resulted in numerous achievements in the pharmaceutical, clinical pharmacologic, and therapeutical sciences. Simultaneously, strenuous efforts have been made in three areas of the natural product chemistry (i) elaboration of a practical semisynthesis of... 

Some of these cytotoxic marine alkaloids are promising candidates for new drugs. For example, ecteinascidins, Fig. (29) are a family of tetrahydroisoquinolone alkaloids isolated from the Caribbean tunicate Ecteinascidici turbinata, which have been selected for clinical development. These compounds are presently in pre-clinical and clinical trials for human cancers [221-225], A series of totally synthetic molecules that are structurally related to the ecteinascidins is currently being prepared and evaluated as antitumor agents [226],... 

The tribrominated bisindole alkaloid dragmacidin (30) from the marine sponge Dragmacidon sp. has antitumor activity against P-388 cells (IC5o 15 pg/ml), A-549 (human lung), HCT-8 (human colon), and MDAMB (human mammary) cancer cell lines (IC501-10 pg/ml) [43]. 

VRLB is a semisynthetic derivative ofVLB (5 -noranhydrovinblastine), structurally distinguished from other members of its class by the modification of the cathar-anthine nucleus rather than the vindoline ring. This alteration is probably responsible for differences in its antitumor activity and tolerability profile compared with other vinca alkaloids [68]. VRLB is effective as monotherapy or in combination with a platinum derivative in patients with advanced NSCLC and advanced breast cancer [69,70]. Myelosuppression is the major dose-limiting toxicity. VRLB is administered weekly nadirs are usually reached within 14 days and patients recover within the next two weeks [71]. VRLB is also well absorbed orally. Oral and i.v. forms show similar interindividual variability, the same metabolism pattern, reproducible intrapatient blood exposure, and the same pharmacokinetic-pharmacodynamic relationship. Given at 60 mg/m /week for the first three administrations and then increased to 80 mg/m /week it achieved the same efficacy as i.v. VRLB (30 mg/m ) in terms of progression-free survival, overall survival, and objective response [70]. 

The indolocarbazole alkaloids and the biosynthetically related bisindolylmaleiraides constitute an important class of natural products, which have been isolated from actinomycetes, cyanobacteria, slime molds, and marine invertebrates [1-3], They display a wide range of biological activities, including antibacterial, antifungal, antiviral, hypotensive, antitumor, and/or neuroprotective properties. The antitumor and neuroprotective activities of indolocarbazoles are the result of one, or several, of the following mechanisms (a) inhibition of different protein kinases, (b) inhibition of DNA topoisomerases, or (c) direct DNA intercalation [3-6], Hundreds of indolocarbazole derivatives have been produced by chemical synthesis or semisynthesis [1,2,6], and several of them have entered clinical trials for the treatment of diverse types of cancer, Parkinson s disease or diabetic retinopathy [3,7]. 

A brominated pyrrole-imidazole alkaloid, rac-dibromophakellstatin, has been shown to display selective antitumor activity in vitro with the highest activity on the ovarian cancer cell line OVXF 899L <2007BMCL346>. The chemistry and bioactivity of anti-tubulin agents, either natural or synthetic, having an indole as core nucleus have been reviewed <2007MI209>. 

Camptothecin (CPT, Cl) is a potent antitumor pentacyclic alkaloid isolated from Camptotheca acuminata Decne. (Nyssaceae family) and originating in China (36, 37). Interest in CPT was sparked by the discovery that its primary cellular target is DNA topo I (38). 10-Hydroxycamptothecin (C2), which also occurs naturally, has a better therapeutic index and is used in China for treating many cancers. 

Rahmani R, Gueritte F, Martin M, Just S, Cano JP, Barbet J. Comparative pharmacokinetics of antitumor vinca alkaloids intravenous bolus injections of Navelbine and related alkaloids to cancer patients and rats. Cancer Chemother Pharmacol 1986 16(3) 223-8. 

Pyrrolizidine alkaloids have long been known to be antitumor active and, more recently, have become of interest as anti-cancer agents. They occur naturally in several plant species, but are often difficult to extract and isolate from the plant material without degradation or the use of toxic solvents. The extraction of a model pyrrolizidine alkaloid, monocrotaline, from the seeds of Crotalaria spectabilis was investigated in this work. 

Also mentioned in the aforecited book are colchicine and colchidnamide, derived from the common autumn crocus (Colchicum autumnale), also called meadow saffron. (Colchicine, incidentally, is used in plant gaieties to artificially produce mutations.) The notable use cited is against breast cancer, but gout and arthritis also yield to treatment. It is emphasized that both these alkaloids are potent, and their use requires expert medical supervision. Another plant mentioned is cro-talaria (Crotalaria spectabilis), from which a toxic alkaloid called monocrotaline may be obtained. This substance also has antitumor properties, but acts against the liver. 

Since 1955, the American National Cancer Institute (NCI) has conducted a massive search for compounds with antitumor activity, with successes including the Vinca alkaloids from the Madagascar periwinkle and taxol from the Pacific yew tree. This highlight [1] covers a family of steroids also discovered by the NCI efforts. 

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