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Combination therapy using oral S-1 and targeted agents against human tumor xenografts in nude mice
Mamoru Nukatsuka1, Hitoshi Saito, Fumio Nakagawa
1Oncology Medical Affairs Division, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194;
Abstract:
In this study, combination therapies using the oral fluoropyrimidine tegafur-gimeracil-oteracil (S-1) with several targeted agents or antibodies, were evaluated. First, the effects of tyrosine kinase inhibitors (erlotinib hydrochloride, sorafenib tosilate and sunitinib malate) against human non-small cell lung cancer (NSCLC), breast cancer and colorectal cancer were evaluated in vivo. The effects of the combination of S-1 and targeted antibodies (bevacizumab and cetuximab) against human colorectal cancers was also evaluated in vivo. S-1 and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, showed a significant inhibition of growth in human NSCLC (Lu-99 and PC-9 cell lines). The antitumor activity of the combination of S-1 and erlotinib against Lu-99 and PC-9 cancer cell lines was significantly superior to either monotherapy (P<0.05). Combination therapy using the multi-tyrosine kinase inhibitors, sorafenib or sunitinib, with S-1 against breast cancer (MX-1 cell line) and NSCLC (NCI-H460 cell line) was significantly superior to either monotherapy (P<0.01). The combination of the anti-vascular endothelial growth factor antibody bevacizumab or the anti-EGFR antibody, cetuximab, with S-1 against human colorectal cancer [Col-1, KM20C (bevacizumab) and DLD-1 (cetuximab) cell lines] and a 5-fluorouracil (5-FU)-resistant cell line (KM12C/5-FU) was significantly superior to either monotherapy (p<0.01). In particular, the growth of the Col-1 cells was completely inhibited by the combination of S-1 and bevacizumab. No toxic mortalities and no significant difference in the body weight changes of the animals treated with S-1 combined with the targeted agents or with the mono-therapies were observed; therefore, the treatments appeared to be well-tolerated. Our preclinical findings indicate that the combination therapies of S-1 and targeted agents are promising treatment options.
Insights
Combination therapies of S-1 with targeted agents like erlotinib, sorafenib, sunitinib, bevacizumab, and cetuximab show superior antitumor activity in preclinical models. These combinations, including S-1 with EGFR inhibitors and antibodies, were well-tolerated and demonstrate promise for cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- The oral fluoropyrimidine tegafur-gimeracil-oteracil (S-1) is a key chemotherapeutic agent.
- Targeted therapies, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, have revolutionized cancer treatment.
- Evaluating combination therapies involving S-1 with novel targeted agents is crucial for improving treatment efficacy.
Purpose of the Study:
- To investigate the efficacy of combination therapies using S-1 with various targeted agents and antibodies against human cancers in preclinical models.
- To assess the synergistic effects of S-1 combined with TKIs (erlotinib, sorafenib, sunitinib) and antibodies (bevacizumab, cetuximab) in non-small cell lung cancer (NSCLC), breast, and colorectal cancers.
- To evaluate the safety and tolerability of these combination regimens.
Main Methods:
- In vivo evaluation of combination therapies in human cancer cell line xenograft models.
- Assessment of the effects of S-1 combined with erlotinib, sorafenib, sunitinib, bevacizumab, and cetuximab.
- Comparison of combination therapy efficacy against monotherapy and assessment of animal body weight changes and mortality.
Main Results:
- S-1 combined with erlotinib demonstrated significant growth inhibition in NSCLC cell lines (Lu-99, PC-9), superior to monotherapy.
- Combinations of S-1 with sorafenib or sunitinib showed significantly superior antitumor activity in breast cancer (MX-1) and NSCLC (NCI-H460) models.
- S-1 plus bevacizumab or cetuximab exhibited significantly superior efficacy in colorectal cancer models, with complete growth inhibition observed in Col-1 cells with S-1 and bevacizumab.
- All tested combination therapies were well-tolerated, with no significant toxicities or adverse effects on animal body weight.
Conclusions:
- Combination therapies of S-1 with targeted agents, including EGFR inhibitors and antibodies, exhibit potent and synergistic antitumor activity in preclinical cancer models.
- These findings support the potential of S-1-based combination strategies as promising therapeutic options for NSCLC, breast, and colorectal cancers.
- The observed tolerability suggests that these combinations could be safely explored in clinical settings.
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