Anti-Tumour Action

Cancer Elevated levels of AEA in glioblastomas, increased levels of 2-AG in meningiomas, elevated levels of both AEA and 2-AG in colorectal carcinoma, with possible anti-tumour action Inhibitors of degradation (both FAAH and cellular re-uptake)... 

Difunctional Alkylating Agents with Anti-Tumour Action.148... 

This correlation between chemical reactivity and anti-tumour action later enabled a rational approach in the design of anti-tumour agents. On the one hand, mustards were synthesised with half-lives of only seconds, for administration directly into arteries supplying the tumour and, on the other hand, agents were prepared with very long half-lives and therefore inactive but which might be selectively metabolised in the tumour to active compounds. 

The initial metabolism of cyclophosphamide is in the liver to the 4-hydroxy-derivative which is in equilibrium with the tautomeric aldehyde 33. It is proposed that selective anti-tumour action would result if normal cells could detoxify this metabolite by enzymatic conversion to known excretory products, the 4-keto or propionic acid derivatives 24 and 28. In the absence of such enzymes the metabolite is known to be unstable and to break down to acrolein 30 and phosphoramide mustard 31, both of which are very toxic to cells in culture66). Selective formation of these toxic breakdown products in tumours that have lost the appropriate detoxifying enzymes could obviously result in toxicity. 

Despite obvious similarities to the bifunctional alkylating agents, the nitrosoureas have a completely different spectrum of anti-tumour action. Although little is known about their mechanism of action, they can break down in vivo... 

Zwi, L. J. (1992) The mechanism of the anti-tumour action of flavone acetic acid and its xanthenone acetic acid analogs. Thesis, The University of Auckland, New Zealand. 

Apart from the understanding of the mechanism of anti-tumour action of cis-[PtCl2(NH3)2l a major interest in the area of nucleic acid-metal ion interactions is the possibility of sequence determination, using specific binding of metal complexes. 

Reedijk J, Fichtinger-Schepman AMJ, Oosterom AT van, Putte P van de (1987) Platinum Amine Coordination Compounds as Anti-Tumour Drugs. Molecular Aspects of the Mechanism of Action. 67 53-89 Rein M, see Schultz H (1991) 74 41-146... 

Oxidation of the phenol ring of cannabidiol (73) or cannabinol to a qui-none ring has been shown to afford compounds with anti-tumour activity. However, these compounds do not bind to the CBi receptor and their mechanism of action is unclear [128],... 

Erba E, Bergamaschi D, Ronzoni S, Faretta M, Tavema S, Bonfanti M, et al. Mode of action of thiocoraline, a natural marine compound with anti-tumour activity. Br. J. Cancer. 1999 Jun 80(7) 971-80. 

The most widely used drug in this category is cisplatin. Therfeore, we have summarized below its action at the chromatin level. The anti-tumour drug cis-diamminedichloroplatinum(II) (cisplatin) is employed for the treatment of ovarian and testicular carcinomas, as well as solid tumours (Loehrer and Einhorn, 1984 Zamble and Lippard 1995). 

New formulations are regularly commercialised. Studies on the action mechanism of 5-FU had a large influence on the development of other anti-tumour drugs derived from pyrimidine and purine. The 5-FU is industrially prepared at important tonnage by fluorination of uracil with elemental fluorine. 

Cytokines which can provide innate protective antiviral (e.g. interferon-a or -(3) and anti-tumour (e.g. tumour necrosis factor—TNF-a) activity against other host cells. A group of cytokines termed chemokines can also serve to chemoattract other leucocytes into an area of ongoing infection or inflammation, for example IL-8 which attracts neutrophils. Yet another group of cytokines has pro-inflammatory actions (e.g. IL-1 and TNF-a) which, among other outcomes, will lead to activation of endothelial and leucocyte cells promoting increased leucocyte extravasation into tissues and in the case of IL-1 activate T-lymphocyte populations. 

The high anti-tumour selectivity of the triazenes and their broad spectrum of action requires further investigation since it may eventually enable the design of agents for clinical use which maintain their anti-tumour specificity but do not break down into products which are toxic but not tumour inhibitory. The role of formaldehyde produced by the active dimethyl derivatives but not by the inactive diethyl analogues, may be important. It has also recently been proposed that toxic products formed by triazenes may be neutralised by factors in the cytoplasm of normal tissues but not in sensitive tumour cells77. ... 

The spiropentane mimics of 2 -deoxyadenosine and 2 -deoxyguanosine (5a,b) have also been synthesised as putative antiviral and anti-tumour agents." They were modest inhibitors of viral replication but could be activated by their conversion to lipophilic phosphoramidate pronucleosides, thus bypassing the first phosphorylation step required by their mode of action. However, the increase in potency was compromised by the amplification of their cytoxicity. 

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