Antitumour cytotoxicity

NFkB activation —> 4-IL-8 MCP-1 expression antibacterial, antifungal, antimigraine, antitumour, cytotoxic]... 

Although tumour growth inhibition by 6-mercaptopurine has been attributed to the inhibition of the conversion of inosinic acid to adenylic acid [309, 310, 312], probably at the first step, this conversion by cell-free extracts from the exquisitely sensitive tumour adenocarcinoma 755 was inhibited only at high levels of 6-mercaptopurine ribonucleotide [313]. Furthermore, hadacidin (A -formylhydroxyaminoacetic acid) is an excellent inhibitor of adenylosuccinate synthetase [314, 315], and yet it has little antitumour activity and is not cytotoxic, showing that this inhibition may be relatively unimportant to cells. 

Ferlini C, Distefano M, Pignatelli F, et al. Antitumour activity of novel taxanes that act at the same time as cytotoxic agents and P-glycoprotein inhibitors. BrJ Cancer 2000 83(12) 1762-1768. 

The dimers were studied more closely in HL-60 leukaemia and Jurkat cell lines, and it was found that they have activities comparable to the clinically nsed anticancer drng doxorubicin. In terms of general toxicity to normal cells, it was observed that dimers 115 and 116 were not toxic to lymphocytes at doses approaching 100 p,M. In preliminary studies, apoptotic cell death was observed on exposnre to these componnds and further studies are ongoing to elucidate the underlying mechanism of apoptosis. For purposes of comparison, the corresponding phosphate ester monomers 117 and 118 were prepared and proved to have no antitumour activity in the cell lines examined. This result is important, because it rules out any role of the phosphate ester functionality in mediating the observed cytotoxic effects and emphasizes the necessity for a bivalent unit. 

The diverse biological activity (allergenic, antitumour, fungitoxic, phytotoxic, cytotoxic, etc.) of germacranolides (226a and b) and other sesquiterpenoids containing cx/S-unsaturated y-butyrolactone units has been reviewed. During the period of... 

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

In the final part of this chapter, we will look at studies where endoperoxides have been investigated for their antitumour potential. There have been a large number of endoperoxide-containing natural products isolated and this has been the focus of some excellent review articles. Countless peroxy natural products have been assayed for various biological properties and many have been found to be cytotoxic to tumour cell lines. 

Schmitz, F. J., Bowden, B. F., and Toth, S. I., Antitumour and cytotoxic compounds from marine organisms, in Marine Biotechnology, Volume 1 Pharmaceutical and Bioactive Natural Products, Attaway, D. H. and Zaborsky, O. R., Eds., Plenum Press, New York, 1993, 197. 

Acridines (Phe pyridine Phe) include arborinine from Ruta graveolens and other Rutaceae (a spasmolytic and A1 adenosine receptor antagonist) and the pyranoquinoline acronycine (with cytotoxic and antitumour activity) from Acronychia species and Melicope leptococca (Rutaceae) and which has become a useful lead compound for the synthesis of other anticancer compounds. A variety of synthetic acridines are DNA binding anticancer compounds. 

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... 

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