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ABSTRACT

Key words: farnesyltransferase; apoptosis; 5-FU; cell cycle; p53The wealth of new knowledge, concerning the molecular and biochemical pathways required for neoplastic transformation, has provided important insights into the clinical behavior of colorectal cancer. It is now widely accepted that the multistep carcinogenic process that is involved in colon cancer is driven by mutational events that ultimately give the cancer cells a growth advantage. 1 Some of these genetic alterations are prognostic factors in colorectal cancer. 2 Molecular alterations also may have the potential to predict survival after chemotherapy. 2,3 Advances in the molecular understanding of normal and pathological disturbed cellular signaling networks may have profound impact on the efficacy of chemotherapy. It has been suggested that modifications of p53, that influence a cell's tendency to apoptosis, may play a significant role in modifying response to radiation and chemotherapy. Cytotoxicity of 5-FU in cell lines of the NCI anticancer drug screening program correlated with their p53 status. 4,5 Disruption in p53, by targeted homologous recombination, rendered human colon cancer cell lines strikingly resistant to the effects of 5-FU. Although alteration of p53 is a plausible predictive factor discrepant results in patients entered in same clinical trials (adjuvant chemotherapy with 5-FU regimen) are reported. 2,3 5-FU cytotoxicity is determined by either thymidine deprivation (inhibition of TS) or by RNA incorporation. Data strongly 6,7 supports the hypothesis that cell death in intestinal epithelia or in human epithelial colon cancer cell lines requires 5-FU metabolites to be incorporated into RNA. Cell death therefore occurs by apoptosis and is p53-dependent. The effects on 5-FU sensitivity were observed both in vitro and in vivo, were independent of p21 waf-1 , and appeared to be the result of alterations in RNA, rather than DNA, metabolism. 8 Recent insights into the biology of colon cancer have spurred development of new drugs [i.e., new folate-based TS inhibitors (Tomudex, AG337 or LY231514), inhibitors of glycinamide ribonucleotide formyltransferase (AG2034, Lemetrexol), Topoisomerase I inhibitors (CPT11) or farnesyltransferase inhibitors (R11577, SCH66336)]. 9,10 Farnesylation is catalyzed by FTase, which is responsible for catalyzing farnesylation of several cellular proteins by transfer a C-15 farnesyl moiety from FPP. Studies have shown that farnesylation of Ras is the obligatory, first step in a series of post-translational modifications that lead to the membrane association that determine the switch from an inactive to an active Ras-GTP bound form. Upon receiving a signal input, Ras-GTP acts as a molecular switch that turns on downstream effectors. [11][12][13][14][15] When farnesylation is blocked, the function of Ras protein is severely impaired because of the inability of the nonfarnesylated protein to anchor to the membrane. All mutant Ras protein involved in human cancer are modified exclusively by FTase, 13 so compound...

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Acetylcholine (Ach), one of the most important examples of a neurotransmitter, represents a phylogenetically old molecule, widely distributed from bacteria to humans. The finding that neuronal Ach receptors (nAChRs) are present in non-neuronal cells raised some interesting issues related to their specific activity. In humans, different studies have showed that many lung cancer cells expressed nAchRs and that low concentrations of nicotine blocked the induction of apoptosis in these cells. A recent study presents data that SCLC express a cholinergic autocrine loop that can regulate cell growth. Such work demonstrates that SCLC cells have a cholinergic phenotype and that ACh exerts as an autocrine growth factor in human lung tumors. Recently it has been shown that human malignant pleural mesothelioma express a cholinergic system, involved in cell growth regulation. Hence, mesothelioma cell growth as well as normal mesothelial cells growth is modulated by the cholinergic system in which agonists (i.e. nicotine) has a proliferative effect and antagonists (i.e. curare) has an inhibitory effect. Furthermore apoptosis mechanisms in mesothelioma cells are under the control of the cholinergic system (nicotine antiapoptotic via induction of NF-kappaB complexes and phosphorilation of Bad at Serine(112), curare proapoptotic via G(0)-G(1) arrest p21(waf-1)-dependent, but p53-independent). The involvement of the non-neuronal cholinergic system in lung cancer and mesothelioma appears reasonable and open up new therapeutic strategies.