TS expression

Thymidylate synthase (TS) is the rate-limiting enzyme in the DNA synthetic pathway and the target for 5-FU and folate analogs (Figure 14.3). Compared to normal tissues, TS is often overexpressed in tumor cells, probably as a result of tumor suppression loss of function, gene amplification or other mechanisms. Acute induction of TS protein as well as stable amplification of TS-specific genes may be associated with resistance to fluoropyrimidine derivatives [118, 119], and an inverse correlation between tumor TS expression and clinical response was found [120-122]. 

In vitro studies have shown that increasing the number of repeats leads to stepwise increases of TS gene expression with the presence of a triple repeat resulting in a 2.6-fold greater TS expression than a double repeat [70, 80]. In vivo studies in human gastrointestinal tumors have shown a significant increase in TS protein levels and functional activity in patients with TSER 3 compared to individuals with TSER 2 [81]. As TS tumor levels are important for resistance and survival prediction, this may have important implications for TS-based chemotherapy. 

An important factor in the resistance to chemotherapy drugs such as 5-fhiorour-acil and Raltitrexed is an increase in TS expression [72, 37]. The TS enhancer region polymorphism may be one mechanism responsible for increasing TS gene expression. 

Although TSER 9 appears to be unique to the Ghanaian population, the sample size evaluated in this study cannot deny the presence of this allele in other African populations [83]. Alleles corresponding to 5-8 or >9 tandem repeats were not identified in this study however, considering the low frequencies of TSER 4 and TSER 9 in the populations studied, it is possible that a larger population study may identify novel alleles. In addition, the significance of TSER 4 and TSER 9 is less clear. An increase in TSER repeats is associated with increased TS expression in vitro and TS protein levels in vivo [70, 80, 81]. There is no data in the literature that evaluates the role of ethnicity in response to TS inhibitor chemotherapy. 

Evans et al did not model VS, however, the TS expression fitted the data fairly well (88% VAC). The significance of the fit of either curve was not improved by altering the values of the coefficients. 

The electron-spin time-correlation functions of Eq. (56) were evaluated numerically by constructing an ensemble of trajectories containing the time dependence of the spin operators and spatial functions, in a manner independent of the validity of the Redfield limit for the rotational modulation of the static ZFS. Before inserting thus obtained electron-spin time-correlation functions into an equation closely related to Eq. (38), Abernathy and Sharp also discussed the effect of distortional/vibrational processes on the electron spin relaxation. They suggested that the electron spin relaxation could be described in terms of simple exponential decay rate constant Ts, expressed as a sum of a rotational and a distortional contribution ... 

A substantial body of evidence has been accumulated in recent years, demonstrating that the level of thymidylate synthase (TS) mRNA and protein expression signifieantly eorrelates with sensitivity and resistance to TS-targeted 5-FU based chemotherapy regimens. However, the cause of the variability in TS expression still remains unelear, even though several molecular mechanisms have been identified that seem to regulate the expression of TS, which may have an impact on the response to 5-FU based chemotherapy. 

These three different polymorphisms in the same gene obviously complicate efforts aimed at imderstanding the effects of each individual polymorphism. TS expression levels, tumor response, and toxicity are functions of multiple TS gene alterations, rather than the result of one single polymorphism. This review will provide an update of the most recent data on 5-FU metabolism and TS gene variations in CRC. 

Most studies have consistently agreed that both, TS mRNA and TS protein expression do vary considerably among tumors and that the respond rate of various tumors towards 5-FU Ijased chemotherapy regimens are related to intratumoral TS mRNA and protein expression. Higher TS expression levels are generally associated with lower response rates and shorter overall survival (3,52,53). 

TS genotypes and their combinations, which have been reported earlier with high TS expression, show longer OS/PFS (3R/3R with ary 3 -UTR genotype and 2R/3R with +6bp/+6bp)... 

The presence of at least one high TS expression genotype showed independent adverse prognostic role in mnltivariant analysis... 

In addition, observations that various tumor characteristics (e.g., TS expression), patient drug-metabolizing enzymes (e.g., DPD and plasma uracihdihydrouracil ratio), and molecular markers (e.g., chromosome 18q allelic loss, microsatellite instability, and p53 muta-... 

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