Topoisomerase I inhibitors camptothecins

Weingart JD, Thompson RC, Tyler B, Colvin OM, Brem H. Local delivery of the topoisomerase I inhibitor camptothecin sodium prolongs survival in the rat intracranial 9L gliosar-coma model. Int J Cancer 1995 62 605-609. 

The major class of topoisomerase I inhibitors comprise of the camptothecins, while topoisomerase II inhibitors fall into several classes - anthracyclines (e.g. doxorubicin), anthracenediones (mitoxantrone), anthrapyrazoles (bianthrazole), actinomycins (actinomycin D), acridines (m-AMSA), ellipticines (9-hydroxy-ellipticine) and epidophyllotoxins (Etoposide (VP-16) and VM-26). The chemical... 

Kohn KW, Pommier Y. Molecular and biological determinants of the cytotoxic actions of camptothecins. Perspective for the development of new topoisomerase I inhibitors. Ann NY Acad Sci 2000 922 11-26. 

The topoisomerase I inhibitors include irinotecan and topotecan. They are water-soluble camptothecin analogues. Both are administered by intravenous infusion. Their cytotoxicity effects are exerted through interaction with the topoisomerase I-DNA complex, eventually leading to cell death. 

Irinotecan is an analogue of camptothecin, a topoisomerase I inhibitor that is used for the treatment of advanced colorectal cancer and a few other solid tumors. Irinotecan is first converted to an active metabolite, SN-38, which is further conjugated into the inactive SN-38 glucuronide (SN-38 G), mainly by UGTIAI, and then eliminated via the bile. A common dinucleotide (TA) repeat polymorphism (containing 5, 6, 7, or 8 copies of TA repeat) has been identified in the UGTIAI promoter TATA box. 

Antimicrotubule inhibitor (M phase) Camptothecins (topoisomerase I inhibitors)... 

The Indian tree Nothapodytes foetida (syn. Mappia foetida) is an important source of camptothecin, the DNA topoisomerase I inhibitor possessing anti-cancer and anti-HIV activity of significant therapeutic importance. One of the minor components of the plant has been identified as 9-methoxy-20-(S)-mappicine, a tetracyclic derivative of the pentacyclic camptothecin. When the latter compound was treated for a short-time (7 min) with microwave irradiation, it was converted into 9-methoxymappicine ketone with an exceptionally high yield of 95%. This ketone was then easily transformed by baker s yeast into the target compound 9-methoxy-20-(S)-mappicine as illustrated in Fig. 15 [91]. 

Czuwara-Ladykowska J, Makiela B, Smith EA, Trojanowska M, Rudnicka L. The inhibitory effects of camptothecin, a topoisomerase I inhibitor, on collagen synthesis in fibroblasts from patients with systemic sclerosis. Arthritis Research 2001, 3,311-318. 

Cositecan (Karenitecin , BNP 1350) 54 (BioNumerik and ASKA Pharmaceutical) is currently being evaluated in a Phase III trial for the treatment of patients with advanced ovarian cancer who have become resistant to platinum and taxane drugs.110 Cositecan 54,111 114 which is also being evaluated against solid tumours in a Phase I trial, is an orally bioavailable, lipophilic 7-[2-(tri-methylsilyl)ethyl] derivative of camptothecin 55 which is less sensitive to both common and camptothecin-specific resistance mechanisms. Camptothecin 55 was first isolated in 1958 from Camptotheca acuminata (Nyssaceae) and its structure was reported in 1966.115 117 Camptothecin 55 was later shown to be a topoisomerase I inhibitor two camptothecin derivatives, topotecan and iri-notecan, are approved for chemotherapy use. 

Camptothecins. The alkaloid camptothecin from Camptotheca acuminata (Nyssaceae) and Mappiafoetida (Icacinaceae) has a pyranoindolizoquinoline structure (Phe pyridine C4N C5N C5L) involving the fusion of quinoline (Phe pyridine), indolizidine (C4N C5N ) and C5 lactone (C5L) rings. Camptothecin is a topoisomerase I inhibitor and is a potent cytotoxic and antitumour compound that is used clinically as an anticancer... 

Covalently linked conjugates, (II), consisting of a topoisomerase I inhibitor such as a camptothecin group and a topoisomerase II inhibitor such as epipodophyllotoxin, were prepared by Lee (1) and used in treating small cell lung cancer. 

Current clinical investigations with topoisomerase I inhibitors include the feasibihty of oral administration of topotecan and irinotecan, the use of a liposomal lurtotecan formulation (NX211), and the use of a pegylated derivative of the naturally occurring camptothecin, which is soluble in aqueous solutions even at low pH values (3,10). 

As noted earlier, the bioassay is capable of detecting topoisomerase I inhibition activity as well as topoisomerase II inhibition activity. It is thus interesting that we found no extracts that showed the topoisomerase I pattern of activity, indicating the scarcity of natural products with this activity and enhancing the uniqueness of camptothecin (12) and its derivatives. Of course, by the same token, the discovery of a new topoisomerase I inhibitor would be a noteworthy event. 

The isoquinoline derivate camptothecin (115), a well known antineoplastic drug and a topoisomerase I inhibitor, showed antiprotozoal activity when tested against L. donovani, T. cruzi and T. b. brucei with EC50 values of 1.5, 1.6 and 3.6 fiM [132, 133]. For these parasites, camptothecin is an important lead for much-needed new chemotherapy, as well as being a valuable tool for further study of topoisomerase I activity. 

The novel DNA topoisomerase I inhibitor, DX-8951f (exatecan mesylate, 264) which does not require metabolic activation is fluorinated, hexacyclic derivative of camptothecin. Compound 264 was reported to be 6- and 28-fold more potent than SN-38 and topotecan, respectively.Compound 264 has shown efficacy in a variety of human mmor xenografts. 

Block copolymer micelles The core is a loading space for hydrophobic drugs, and the shell is a hydrophilic corona that makes the micelle water soluble, thereby allowing delivery of the poorly soluble contents For delivery of camptothecin, a topoisomerase I inhibitor that is effective against cancer but insoluble 27... 

DNA synthesis/mitotic inhibitors Irinotecan Irinotecan is a drug that has been studied more recently within the context of malignant CNS tumors, especially in concert with bevicizumab (discussed below). Irinotecan is a semisynthetic derivative of camptothecin, a topoisomerase I inhibitor. Irinotecan binds and stabilizes topoisomerase-DNA complexes, preventing the unwinding of DNA, thereby causing irreparable DNA double-strand breaks and eventually cell death. 

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