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Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer.

Takezawa K, Okamoto I, Okamoto W, Takeda M, Sakai K, Tsukioka S, Kuwata K, Yamaguchi H, Nishio K, Nakagawa K - Br. J. Cancer (2011)

Bottom Line: The sensitivity of NSCLC cells overexpressing TS to the antiproliferative effect of pemetrexed was markedly reduced compared with that of control cells.Finally, the level of TS expression in tumours of non-responding patients was significantly higher than that in those of responders, suggestive of an inverse correlation between TS expression and tumour response to pemetrexed.A high level of TS expression confers a reduced sensitivity to pemetrexed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.

ABSTRACT

Background: Although a high level of thymidylate synthase (TS) expression in malignant tumours has been suggested to be related to a reduced sensitivity to the antifolate drug pemetrexed, no direct evidence for such an association has been demonstrated in non-small cell lung cancer (NSCLC). We have now investigated the effect of TS overexpression on pemetrexed sensitivity in NSCLC cells.

Methods: We established NSCLC cell lines that stably overexpress TS and examined the effects of such overexpression on the cytotoxicity of pemetrexed both in vitro and in xenograft models. We further examined the relation between TS expression in tumour specimens from NSCLC patients and the tumour response to pemetrexed by immunohistochemical analysis.

Results: The sensitivity of NSCLC cells overexpressing TS to the antiproliferative effect of pemetrexed was markedly reduced compared with that of control cells. The inhibition of DNA synthesis and induction of apoptosis by pemetrexed were also greatly attenuated by forced expression of TS. Furthermore, tumours formed by TS-overexpressing NSCLC cells in nude mice were resistant to the growth-inhibitory effect of pemetrexed observed with control tumours. Finally, the level of TS expression in tumours of non-responding patients was significantly higher than that in those of responders, suggestive of an inverse correlation between TS expression and tumour response to pemetrexed.

Conclusion: A high level of TS expression confers a reduced sensitivity to pemetrexed. TS expression is thus a potential predictive marker for response to pemetrexed-based chemotherapy in NSCLC patients.

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Relation of TS expression level to tumour response in NSCLC patients treated with pemetrexed and either carboplatin or cisplatin. (A) Representative sections of carcinomas including cells with the indicated intensities of TS immunostaining. Scale bars, 125 μm. (B) TS expression level (HSCORE) for the clinical specimens of 24 patients classified according to tumour response (response=CR or PR, n=7; non-response=SD or PD, n=17). Horizontal lines indicate mean values. The P value was determined by Student's two-tailed t test. (C) Progression-free survival of the NSCLC patients according to the expression level of TS in tumour specimens. The P-value was determined with the log-rank test.
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fig6: Relation of TS expression level to tumour response in NSCLC patients treated with pemetrexed and either carboplatin or cisplatin. (A) Representative sections of carcinomas including cells with the indicated intensities of TS immunostaining. Scale bars, 125 μm. (B) TS expression level (HSCORE) for the clinical specimens of 24 patients classified according to tumour response (response=CR or PR, n=7; non-response=SD or PD, n=17). Horizontal lines indicate mean values. The P value was determined by Student's two-tailed t test. (C) Progression-free survival of the NSCLC patients according to the expression level of TS in tumour specimens. The P-value was determined with the log-rank test.

Mentions: To evaluate the relation between the level of TS expression in NSCLC tumours and the clinical response to pemetrexed, we performed semiquantitative immunohistochemical analysis on tumour biopsy specimens from 24 patients with advanced NSCLC treated with pemetrexed combined with platinum agents (Figure 6A). The characteristics of the patients are shown in Table 2. Tumours were categorised as either responding (CR or PR) or non-responding (SD or PD). The level of TS expression for non-responding groups was significantly (P=0.038) higher than that for responding groups (Figure 6B). We next carried out ROC curve analysis to establish the optimal cutoff value for the HSCORE of TS expression level, yielding a value of 257.5. Patients with a low level of TS expression (HSCORE<257.5) had a significantly longer progression-free survival (P=0.014) than did those with a high level (HSCORE⩾257.5) (Figure 6C). These data thus suggested that TS expression level in advanced NSCLC tumours is inversely correlated with the response to pemetrexed.


Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer.

Takezawa K, Okamoto I, Okamoto W, Takeda M, Sakai K, Tsukioka S, Kuwata K, Yamaguchi H, Nishio K, Nakagawa K - Br. J. Cancer (2011)

Relation of TS expression level to tumour response in NSCLC patients treated with pemetrexed and either carboplatin or cisplatin. (A) Representative sections of carcinomas including cells with the indicated intensities of TS immunostaining. Scale bars, 125 μm. (B) TS expression level (HSCORE) for the clinical specimens of 24 patients classified according to tumour response (response=CR or PR, n=7; non-response=SD or PD, n=17). Horizontal lines indicate mean values. The P value was determined by Student's two-tailed t test. (C) Progression-free survival of the NSCLC patients according to the expression level of TS in tumour specimens. The P-value was determined with the log-rank test.
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Related In: Results  -  Collection

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fig6: Relation of TS expression level to tumour response in NSCLC patients treated with pemetrexed and either carboplatin or cisplatin. (A) Representative sections of carcinomas including cells with the indicated intensities of TS immunostaining. Scale bars, 125 μm. (B) TS expression level (HSCORE) for the clinical specimens of 24 patients classified according to tumour response (response=CR or PR, n=7; non-response=SD or PD, n=17). Horizontal lines indicate mean values. The P value was determined by Student's two-tailed t test. (C) Progression-free survival of the NSCLC patients according to the expression level of TS in tumour specimens. The P-value was determined with the log-rank test.
Mentions: To evaluate the relation between the level of TS expression in NSCLC tumours and the clinical response to pemetrexed, we performed semiquantitative immunohistochemical analysis on tumour biopsy specimens from 24 patients with advanced NSCLC treated with pemetrexed combined with platinum agents (Figure 6A). The characteristics of the patients are shown in Table 2. Tumours were categorised as either responding (CR or PR) or non-responding (SD or PD). The level of TS expression for non-responding groups was significantly (P=0.038) higher than that for responding groups (Figure 6B). We next carried out ROC curve analysis to establish the optimal cutoff value for the HSCORE of TS expression level, yielding a value of 257.5. Patients with a low level of TS expression (HSCORE<257.5) had a significantly longer progression-free survival (P=0.014) than did those with a high level (HSCORE⩾257.5) (Figure 6C). These data thus suggested that TS expression level in advanced NSCLC tumours is inversely correlated with the response to pemetrexed.

Bottom Line: The sensitivity of NSCLC cells overexpressing TS to the antiproliferative effect of pemetrexed was markedly reduced compared with that of control cells.Finally, the level of TS expression in tumours of non-responding patients was significantly higher than that in those of responders, suggestive of an inverse correlation between TS expression and tumour response to pemetrexed.A high level of TS expression confers a reduced sensitivity to pemetrexed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.

ABSTRACT

Background: Although a high level of thymidylate synthase (TS) expression in malignant tumours has been suggested to be related to a reduced sensitivity to the antifolate drug pemetrexed, no direct evidence for such an association has been demonstrated in non-small cell lung cancer (NSCLC). We have now investigated the effect of TS overexpression on pemetrexed sensitivity in NSCLC cells.

Methods: We established NSCLC cell lines that stably overexpress TS and examined the effects of such overexpression on the cytotoxicity of pemetrexed both in vitro and in xenograft models. We further examined the relation between TS expression in tumour specimens from NSCLC patients and the tumour response to pemetrexed by immunohistochemical analysis.

Results: The sensitivity of NSCLC cells overexpressing TS to the antiproliferative effect of pemetrexed was markedly reduced compared with that of control cells. The inhibition of DNA synthesis and induction of apoptosis by pemetrexed were also greatly attenuated by forced expression of TS. Furthermore, tumours formed by TS-overexpressing NSCLC cells in nude mice were resistant to the growth-inhibitory effect of pemetrexed observed with control tumours. Finally, the level of TS expression in tumours of non-responding patients was significantly higher than that in those of responders, suggestive of an inverse correlation between TS expression and tumour response to pemetrexed.

Conclusion: A high level of TS expression confers a reduced sensitivity to pemetrexed. TS expression is thus a potential predictive marker for response to pemetrexed-based chemotherapy in NSCLC patients.

Show MeSH
Related in: MedlinePlus