• Tuberculosis and Respiratory Diseases
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• v.67 no.3
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• pp.191-198
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• 2009

Background: Pemetrexed, a multi-targeted antifolate has been used as a second line treatment against non-small cell lung cancer (NSCLC). We aimed to clarify the efficacy and survival according to line of treatment, histologic type, and expression of thymidylate synthase (TS). Methods: Ninety-eight patients were treated with pemetrexed as a second line treatment (n=43) or as an additional course of treatment (n=55). TS expression was studied with immunohistochemistry and graded as 0 to 3 based on the extent of expression. Results: The response rate (RR) in 98 subjects was 10.2% and the disease control rate (DCR=PR+SD) was 30.6%. RR and DCR were 12.7% and 32.7% in non-squamous cell carcinoma (NSQC) compared to 7.0% and 27.9% in squamous cell carcinoma (SQC) (p>.05). No significant differences in RR and DCR were observed between a second line group (4.7%, 20.9%) and a further line group (14.5%, 38.2%). A similar trend was observed in the 88 response evaluable subjects. TS was expressed in 28.6% (grade 1), 24.5% (grade 2) and 7.1% (grade 3), respectively, and it was not expressed in 39.8% of subjects. TS expression rate was significantly higher in the SQC (72.1%) compared to NSQC (50.9%, p=0.033). However, the efficacy of pemetrexed was not significantly different by the extent of TS expression. Conclusion: Pemetrexed showed efficacy, not only in a second-line setting, but also in further lines of treatment for NSCLC. The efficacy of pemetrexed tended to be higher in patients with NSQC compared to SQC. TS expression rate was significantly higher in SQC compared to NSQC.

• Parasites, Hosts and Diseases
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• v.36 no.3
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• pp.191-198
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• 1998

The responses to antifolales of ToxopLasmc Bondii were investigated by measuring the dihydrorolate redLlctase (DHFR) activity. quantity of DHFR mRNA, and single-strand conformational polymorphism (SSCP) pattern. Pyrimethamine (PYM) and methotrexate (MTX) were tested ds anlifolates. When T. gondii was treated wish PYM, the viability was decreased by the increasing concentration of PYM. DHFR activity tended to increase as the passage proceeded. and the quantity of mRNA expressed was also increased according to passages. The viability of 7. gonnii was decreased by the increasing concentration of MTX, but it was maintained over 40% up to $100{\;}{\mu\textrm{m}}$ MTX. DHFR activity was 77.4% in the 1st passage ($1{\;}{\mu\textrm{m}}$). 82.2% in the 4th passage ($10{\;}{\mu\textrm{m}}$), and 141.3% in the 7th passage ($100{\;}{\mu\textrm{m}}$) But no changes were detected in SSCP pattern of T gondii rxposvd to FYM and MTX. both. These results suggested that the response of T gondii to FYN was rofulalcd by transrriptional level and that, in MTX. the viability of T. gonnii was derived from increasing DHFK activity.

• Journal of Life Science
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• v.20 no.1
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• pp.103-112
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• 2010

Pemetrexed has demonstrated clinical activity in non-small cell lung cancer (NSCLC) as well as other solid tumors. It transports into the cells via reduced folate carrier (RFC) and is polyglutamated by folypolyglutamate synthetase (FPGS). Pemetrexed directly inhibits several folate-dependent enzymes such as thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). We investigated the effects of genetic variations and the expression of RFC, FPGS, TS and DHFR enzymes on drug sensitivity to pemetrexed in NSCLC cells. Polymorphisms in RFC, FPGS, and DHFR were genotyped in four NSCLC cells - A549, PC14, HCC-1588, and H226. Real-time RT-PCR and Western blot was performed to evaluate mRNA transcripts and protein of these genes. The cytotoxicity of pemetrexed was measured by SRB assay. In PC14 and H226 cells, increased mRNA expressions of RFC and FPGS were associated with higher cytotoxicity to pemetrexed. 2R/2R genotype of TS and its increased mRNA expression were associated with drug resistance to pemetrexed in A549 cells, whereas 3R/3R genotype in TS with decreased mRNA expression was associated with higher sensitivity in H226 cells. After pemetrexed treatment, an inverse change of DHFR mRNA and protein expression was found. The strongest linkage disequilibrium (LD) was discovered between-1726C>T and -1188A>C SNP of DHFR gene. Our findings suggest the cytotoxic effect of pemetrexed may be associated with genetic polymorphisms and the expression level of genes involved in pemetrexed metabolisms in NSCLC cells.