臺灣博碩士論文加值系統

開發有效的癌症療法仍然是科學家及醫生的一大挑戰，為了開發癌症藥物，於是提出許多針對癌症治療相關的假說，現今的假說著重在個人化醫學及精準醫學，所以癌症標靶癌症成為研究的主流，近期的研究也發現，針對癌症抑制免疫細胞的特性著手在癌症治療上，是具有潛力的。藥物組合療法常常用於治療感染性疾病，現今癌症治療也漸漸往藥物組合療法為主流，因為藥物組合療法的治療緩解率相對於單一藥物療法來得更好，然而，為了確保療效，癌症的藥物組合療法通常使用高劑量化療藥物作組合，這樣的高劑量會導致許多嚴重的副作用像是骨髓抑制或甚至是神經毒性，為了能夠降低這些副作用並且維持原有的療效，我們想利用藥物的協同作用來開發低劑量藥物組合療法。依照我們開發的研究平台，我們順利找出31種有效抑制大腸直腸癌細胞株的藥物，大多是抗癌藥物，然而有些治療轉移性大腸直腸癌的藥物並未篩選出來。我們發現，同種類型的藥物擁有相似的癌細胞抑制率，根據希爾方程式計算出的希爾係數，也發現這些藥物有相似的希爾係數，也代表了他們有相類似的結合協同性。我們也發現，有些藥物，即使在接近無效劑量的處理下，也可以大大改變其他藥物的劑量效應曲線，雖然，大多數的藥物組合之間大多沒有協同作用，甚至還有相互拮抗的現象發生。最後，我們懷疑協同作用具有細胞特異性並加以實驗佐證，這樣的細胞特異性會造成藥物組合療法開發的困難，還需要更進一步的釐清與解決問題。

Development of effective therapy against malignant tumors remains a grand challenge. Various hypotheses have been proposed for drug discovery for cancers. Currently, targeted therapy against driver oncogenes/oncoproteins is the mainstay of the anti-cancer therapy. Recently, interference of suppression of immune cells on cancers has shown some promise. Combination therapies are widely used against infectious diseases. Here, we first established a workflow to identify the chemical components that can be used in the combination therapy, which uncovered more than thirty compounds with strong activity in suppression of colorectal carcinoma (CRC) cell growth. While some anti-CRC chemotherapeutic agents in clinical practice are not included, 5-FU and irinotecan are indeed enlisted. Antineoplastics from the same class usually have similar potency in CRC inhibition as well as therapeutic cooperativity based on evaluation of their Hill coefficients in cell suppression. We also found that a group of compounds used for other indications can effectively suppress CRC cell growth. Co-treatment with certain antineoplastic at sub-effective doses can drastically change the dose-response curves of others. However, the change is only seen with particular chemical pairings, since most combinations lack any synergism and some may even give mutual antagonism. Finally, we suspect that the synergism is sometimes a cell-dependent phenomenon, and such an idiosyncrasy should be verified in development of antineoplastic cocktails.

致謝 i
中文摘要 ii
ABSTRACT iii
TABLE OF CONTENTS iv
LIST OF TABLES v
LIST OF FIGURES vi
LIST OF ABBREVIATIONS ix
CHAPTER I 1
1. Introduction of colorectal carcinoma 2
2. Challenges of cancer treatment 12
3. Combination therapies in cancer treatment 23
CHAPTER II 28
SUMMARY 29
INTRODUCTION 30
MATERIAL AND METHODS 32
RESULTS 35
Figure 1. Summary of compound with cytotoxicity to colorectal carcinoma cells 37
Table 1. The classes of compounds with capacity to suppress MTT activity of colorectal cancer cell lines 38
Figure 2. MTT activity of HCT116 cells in the presence of daunorubicin and doxorubicin at various doses 40
Figure 3. MTT activity of HCT116 cells in the presence of idarubicin and epirubicin at various doses 41
Figure 4. MTT activity of HCT116 cells in the presence of the indicated antimetabolite compound as an antineoplastic at various doses 43
Figure 5. MTT activity of HCT116 cells in the presence of the indicated antimetabolite compound as an antineoplastic at various doses 44
Figure 6. MTT activity of HCT116 cells in the presence of the indicated vinca alkaloid as an antineoplastic at various doses 45
Figure 7. MTT activity of HCT116 cells in the presence of the indicated camptothecin compounds as antineoplastics at various doses 47
Figure 8. MTT activity of HCT116 cells in the presence of the indicated antimicrotubular antineoplastic at various doses 48
Figure 9. MTT activity of HCT116 cells in the presence of the indicated HDAC inhibitor as an antineoplastic at various doses 49
Figure 10. MTT activity of HCT116 cells in the presence of the indicated proteasome inhibitor as an antineoplastic at various doses 50
Figure 11. MTT activity of HCT116 cells in the presence of the indicated antibiotic as an antineoplastic at various doses 51
Figure 12. MTT activity of HCT116 cells in the presence of the indicated immunosuppressants as antineoplastics at various doses 54
Figure 13. MTT activity of HCT116 cells in the presence of the indicated anthelminticsas at various doses 55
Figure 14. MTT activity of HCT116 cells in the presence of the indicated antibiotic at various doses 56
Figure 15. MTT activity of HCT116 cells in the presence of the indicated antidysrhythmic at various doses 57
Figure 16. MTT activity of HCT116 cells in the presence of the indicated antifungal at various doses 58
Figure 17. MTT activity of HCT116 cells in the presence of the indicated antirheumatic at various doses 59
Figure 18. MTT activity of HCT116 cells in the presence of the indicated keratolytic at various doses 60
Figure 19. MTT activity of HCT116 cells in the presence of the indicated uricosuric at various doses 61
Figure 20. MTT activity of HCT116 cells at various concentrations of albendazole in the presence of low-dose paclitaxel 64
Figure 21. MTT activity of HCT116 cells at various concentrations of albendazole in the presence of low-dose vincristine 65
Figure 22. MTT activity of HCT116 cells at various concentrations of vinorebine (upper) or gemcitabine (lower) in the presence of low-dose vincristine 66
Figure 23. MTT activity of HCT116 cells at various concentrations of vinorelbine (upper) or bortezomib (lower) in the presence of the other compound at a sub-effective dose 67
DISCUSSION 68
Figure 24. MTT activity of HCT116 and LS1034 cells in the presence of a particular compound at different dosages 70
REFERENCES 74

Ahlquist, D. A., Sargent, D. J., Loprinzi, C. L., Levin, T. R., Rex, D. K., Ahnen, D. J., Knigge, K., Lance, M. P., Burgart, L. J., & Hamilton, S. R. (2008). Stool DNA and occult blood testing for screen detection of colorectal neoplasia. Annals of internal medicine, 149(7), 441-450.
Akkoca, A. N., Yanık, S., Özdemir, Z. T., Cihan, F. G., Sayar, S., Cincin, T. G., Çam, A., & Özer, C. (2014). TNM and Modified Dukes staging along with the demographic characteristics of patients with colorectal carcinoma. International journal of clinical and experimental medicine, 7(9), 2828.
Arkenau, H. T., Bermann, A., Rettig, K., Strohmeyer, G., & Porschen, R. (2003). 5-Fluorouracil plus leucovorin is an effective adjuvant chemotherapy in curatively resected stage III colon cancer: long-term follow-up results of the adjCCA-01 trial. Annals of oncology, 14(3), 395-399.
Arnold, C. N., Goel, A., & Boland, C. R. (2003). Role of hMLH1 promoter hypermethylation in drug resistance to 5‐fluorouracil in colorectal cancer cell lines. International journal of cancer, 106(1), 66-73.
Baird, R., Biondo, A., Chhaya, V., McLachlan, J., Karpathakis, A., Rahman, S., Barbachano, Y., Cunningham, D., & Chau, I. (2011). Toxicity associated with capecitabine plus oxaliplatin in colorectal cancer before and after an institutional policy of capecitabine dose reduction. British journal of cancer, 104(1), 43.
Bizzarri, N., Ghirardi, V., Alessandri, F., Venturini, P. L., Valenzano Menada, M., Rundle, S., Leone Roberti Maggiore, U., & Ferrero, S. (2016). Bevacizumab for the treatment of cervical cancer. Expert opinion on biological therapy, 16(3), 407-419.
Brenner, H., Kloor, M. and Pox, C.P. (2014) Colorectal Cancer. The Lancet, 383, 1490-1502.
Cao, W., Yang, W., Lou, G., Jiang, J., Geng, M., Xi, W., Li, H., Ma, T., & Jin, Y. (2009). Phase II trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) as first-line treatment for advanced gastric cancer. Anti-cancer drugs, 20(4), 287-293.
Casadaban, L., Rauscher, G., Aklilu, M., Villenes, D., Freels, S., & Maker, A. V. (2016). Adjuvant chemotherapy is associated with improved survival in patients with stage II colon cancer. Cancer, 122(21), 3277-3287.
Chabot, G. G. (1997). Clinical pharmacokinetics of irinotecan clinical pharmacokinetics, 33(4), 245-259. l
Cheong, K., Spicer, J., Chowdhury, S., & Harper, P. (2005). Combination therapy versus single agent chemotherapy in non-small cell lung cancer. Expert opinion on pharmacotherapy, 6(10), 1693-1700.
Chopra, D., Rehan, H. S., Sharma, V., & Mishra, R. (2016). Chemotherapy-induced adverse drug reactions in oncology patients: a prospective observational survey. Indian journal of medical and paediatric oncology: official journal of Indian Society of Medical & Paediatric Oncology, 37(1), 42.
Chou, T. C. (2010). Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer research, 0008-5472.
Constenla, M., Garcia-Arroyo, R., Lorenzo, I., Carrete, N., Campos, B., & Palacios, P. (2002). Docetaxel, 5-fluorouracil, and leucovorin as treatment for advanced gastric cancer: results of a phase II study. Gastric cancer, 5(3), 0142-0147.
Cunningham, D., Humblet, Y., Siena, S., Khayat, D., Bleiberg, H., Santoro, A., Bets, D., Mueser, M., Harstrick, A., & Verslype, C. (2004). Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New England journal of medicine, 351(4), 337-345.
Cunningham, D., Maroun, J., Vanhoefer, U., & Van Cutsem, E. (2001). Optimizing the use of irinotecan in colorectal cancer. The Oncologist, 6(Supplement 4), 17-23.
De Lavallade, H., Khoder, A., Hart, M., Sarvaria, A., Sekine, T., Alsuliman, A., Mielke, S., Bazeos, A., Stringaris, K., and Ali, S. (2013). Tyrosine kinase inhibitors impair B cell immune responses in CML through off-target inhibition of kinases important for cell signaling. Blood, blood-2012.
De Roock, W., De Vriendt, V., Normanno, N., Ciardiello, F., & Tejpar, S. (2011). KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. The lancet oncology, 12(6), 594-603.
Ding, Y., Xuan, W., Chen, C., Chen, Z., Yang, Z., Zuo, Y., & Ren, S. (2014). Differences in carcinoembryonic antigen levels between colon and rectal cancer. Molecular and clinical oncology, 2(4), 618-622.
Duffy, A. G., & Greten, T. F. (2013). Immunological off-target effects of standard treatments in gastrointestinal cancers. Annals of oncology, 25(1), 24-32.
Duineveld, L. A., van Asselt, K. M., Bemelman, W. A., Smits, A. B., Tanis, P. J., van Weert, H. C., & Wind, J. (2016). Symptomatic and asymptomatic colon cancer recurrence: a multicenter cohort study. The Annals of Family Medicine, 14(3), 215-220.
Dukes, C. E. (1932). The classification of cancer of the rectum. The Journal of Pathology and Bacteriology, 35(3), 323-332.
Eliopoulos, A. G., Kerr, D. J., Herod, J., Hodgkins, L., Krajewski, S., Reed, J. C., & Young, L. S. (1995). The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2. Oncogene, 11(7), 1217-1228.
Elmore, S. (2007). Apoptosis: a review of programmed cell death. Toxicologic pathology, 35(4), 495-516.
Fakih, M. G. (2004). 5-fluorouracil leucovorin and oxaliplatin (FOLFOX) in the treatment of metastatic colon cancer with severe liver dysfunction. Oncology, 67(3-4), 222-224.
Fang, S., & Fang, X. (2016). Advances in glucose metabolism research in colorectal cancer. Biomedical reports, 5(3), 289-295.
Folprecht, G., Cunningham, D., Ross, P., Glimelius, B., Di Costanzo, F., Wils, J., Scheithauer, W., Rougier, P., Aranda, E., & Hecker, H. (2004). Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: a pooled analysis of clinical trials. Annals of Oncology, 15(9), 1330-1338.
Forones, N. M., & Tanaka, M. (1999). CEA and CA 19-9 as prognostic indexes in colorectal cancer. Hepato-gastroenterology, 46(26), 905-908.
Gazdar, A. (2009). Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene, 28(S1), S24.
Geng, F., Wang, Z., Yin, H., Yu, J., & Cao, B. (2017). Molecular targeted drugs and treatment of colorectal cancer: recent progress and future perspectives. Cancer biotherapy & radiopharmaceuticals, 32(5), 149-160.
Gillet, J. P., & Gottesman, M. M. (2010). Mechanisms of multidrug resistance in cancer. In Multi-drug resistance in cancer (pp. 47-76). Humana Press.
Goldberg, R. M., Fleming, T. R., Tangen, C. M., Moertel, C. G., Macdonald, J. S., Haller, D. G., & Laurie, J. A. (1998). Surgery for recurrent colon cancer: strategies for identifying resectable recurrence and success rates after resection. Annals of internal medicine, 129(1), 27-35.
Gomez, D., De Rosa, A., Addison, A., Brooks, A., Malik, H. Z., & Cameron, I. C. (2013). Cetuximab therapy in the treatment of metastatic colorectal cancer: The future frontier?. International Journal of Surgery, 11(7), 507-513.
Gong, J., Cho, M., & Fakih, M. (2016). RAS and BRAF in metastatic colorectal cancer management. Journal of gastrointestinal oncology, 7(5), 687.
Hata, T., Takahashi, H., Sakai, D., Haraguchi, N., Nishimura, J., Kudo, T., Chu, M., Takemasa, I., Taroh, S., & Mizushima, T. (2017). Neoadjuvant CapeOx therapy followed by sphincter-preserving surgery for lower rectal cancer. Surgery today, 47(11), 1372-1377.
Havelka, A. M., Berndtsson, M., Olofsson, M. H., Shoshan, M. C., & Linder, S. (2007). Mechanisms of action of DNA-damaging anticancer drugs in treatment of carcinomas: is acute apoptosis an “off-target” effect?. Mini reviews in medicinal chemistry, 7(10), 1035-1039.
Hirsh, V. (2011). Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Current Oncology, 18(3), 126.
Hirte, H., Kennedy, E. B., Elit, L., & Fung, M. F. K. (2015). Systemic therapy for recurrent, persistent, or metastatic cervical cancer: a clinical practice guideline. Current Oncology, 22(3), 211.
Jeon, E. K., Hong, S. H., Kim, T. H., Jung, S. E., Park, J. C., Won, H.-S., Ko, Y.-H., Rho, S. Y., & Hong, Y. S. (2011). Modified FOLFIRI as second-line chemotherapy after failure of modified FOLFOX-4 in advanced gastric cancer. Cancer research and treatment: official journal of Korean Cancer Association, 43(3), 148.
Ji, Y., Gu, J., Makhov, A. M., Griffith, J. D., & Mitchell, B. S. (2006). Regulation of the interaction of inosine monophosphate dehydrogenase with mycophenolic acid by GTP. Journal of Biological Chemistry, 281(1), 206-212.
Johnston, P. G., & Kaye, S. (2001). Capecitabine: a novel agent for the treatment of solid tumors. Anti-cancer drugs, 12(8), 639-646.
Jortani, S. A., Helm, R. A., & Valdes, R. (1996). Inhibition of Na, K-ATPase by oleandrin and oleandrigenin, and their detection by digoxin immunoassays. Clinical chemistry, 42(10), 1654-1658.
Kim, S. Y., Jung, S. K., Lee, S. G., Yi, S. M., Kim, J. H., & Kim, I. H. (2013). New alternative combination therapy for recalcitrant common warts: the efficacy of imiquimod 5% cream and duct tape combination therapy. Annals of dermatology, 25(2), 261-263.
Konishi, T., Sasaki, S., Watanabe, T., Kitayama, J., & Nagawa, H. (2005). Exogenous expression of hRFI induces multidrug resistance through escape from apoptosis in colorectal cancer cells. Anticancer research, 25(4), 2737-2741.
Labianca, R., Pessi, M. A., & Zamparelli, G. (1997). Treatment of colorectal cancer. Current guidelines and future prospects for drug therapy. Drugs, 53(4), 593.
Levi, F., Zidani, R., & Misset, J. L. (1997). Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. The Lancet, 350(9079), 681-686.
Lewis, A., Forrester, L., Hayes, J., Wareing, C., Carmichael, J., Harris, A., Mooghen, M., & Wolf, C. (1989). Glutathione S-transferase isoenzymes in human tumours and tumour derived cell lines. British journal of cancer, 60(3), 327.
Longley, D. B., Harkin, D. P., & Johnston, P. G. (2003). 5-fluorouracil: mechanisms of action and clinical strategies. Nature Reviews Cancer, 3(5), 330.
Matsushita, H., Tsuboi, K., Honda, I., Kato, N., Okochi, O., Kobayashi, D., & Hattori, M. (2009). The efficacy and toxicity of FOLFOX regimen (a combination of leucovorin and fluorouracil with oxaliplatin) as first-line treatment of metastatic colorectal cancer. Gan to kagaku ryoho. Cancer & chemotherapy, 36(5), 797-801.
McFadyen, M. C., McLeod, H. L., Jackson, F. C., Melvin, W. T., Doehmer, J., & Murray, G. I. (2001). Cytochrome P450 CYP1B1 protein expression:: A novel mechanism of anticancer drug resistance1. Biochemical pharmacology, 62(2), 207-212.
McNair, A. G., Whistance, R. N., Forsythe, R. O., Macefield, R., Rees, J., Pullyblank, A. M., Avery, K. N., Brookes, S. T., Thomas, M. G., & Sylvester, P. A. (2016). Core outcomes for colorectal cancer surgery: a consensus study. PLoS medicine, 13(8), e1002071.
Miles, D., von Minckwitz, G., & Seidman, A. D. (2002). Combination versus sequential single-agent therapy in metastatic breast cancer. The oncologist, 7(Supplement 6), 13-19.
Millan, M., Merino, S., Caro, A., Feliu, F., Escuder, J., & Francesch, T. (2015). Treatment of colorectal cancer in the elderly. World journal of gastrointestinal oncology, 7(10), 204.
Moreau, L. C., Rajan, R., Thirlwell, M. P., & Alcindor, T. (2013). Response to chemotherapy in metastatic colorectal cancer after exposure to oxaliplatin in the adjuvant setting. Anticancer research, 33(4), 1765-1768.
Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of immunological methods, 65(1-2), 55-63.
Nagata, Y., Lan, K.-H., Zhou, X., Tan, M., Esteva, F. J., Sahin, A. A., Klos, K. S., Li, P., Monia, B. P., & Nguyen, N. T. (2004). PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer cell, 6(2), 117-127.
Nakayama, G., Ishigure, K., Yokoyama, H., Uehara, K., Kojima, H., Ishiyama, A., Hayashi, N., Takano, N., Hattori, N., & Kobayashi, D. (2017). The efficacy and safety of CapeOX plus bevacizumab therapy followed by capecitabine plus bevacizumab maintenance therapy in patients with metastatic colorectal cancer: a multi-center, single-arm, phase II study (CCOG-0902). BMC cancer, 17(1), 243.
Oguri, T., Kunii, E., Fukuda, S., Sone, K., Uemura, T., Takakuwa, O., Kanemitsu, Y., Ohkubo, H., Takemura, M., & Maeno, K. (2016). Organic cation transporter 6 directly confers resistance to anticancer platinum drugs. Biomedical reports, 5(5), 639-643.
Pagliara, V., Saide, A., Mitidieri, E., di Villa, B. R. D. E., Sorrentino, R., Russo, G., & Russo, A. (2016). 5-FU targets rpL3 to induce mitochondrial apoptosis via cystathionine-β-synthase in colon cancer cells lacking p53. Oncotarget, 7(31), 50333.
Pasetto, L. M., Jirillo, A., Iadicicco, G., Rossi, E., Paris, M. K., & Monfardini, S. (2005). FOLFOX versus FOLFIRI: a comparison of regimens in the treatment of colorectal cancer metastases. Anticancer research, 25(1B), 563-576.
Peng, L., Wang, Y., Tang, Y., Zeng, L., Liu, J., Zeng, Z., Liu, J., Shi, P., Ye, X., & Zhao, Q (2017). Continuous EGFR tyrosine kinase inhibitor treatment with or without chemotherapy beyond gradual progression in non-small cell lung cancer patients. OncoTargets and therapy, 10, 4261.
Penna, C., & Nordlinger, B. (2002). Colorectal metastasis (liver and lung). The Surgical clinics of North America, 82(5), 1075-90.
Petrelli, F., Ardito, R., Ghidini, A., Zaniboni, A., Ghidini, M., Barni, S., & Tomasello, G. (2018). Different Toxicity of Cetuximab and Panitumumab in Metastatic Colorectal Cancer Treatment: A Systematic Review and Meta-Analysis. Oncology, 94(4), 191-199.
Petrioli, R., Francini, E., Cherri, S., Torre, P., Fiaschi, A. I., Miano, S. T., Marrelli, D., Rovello, F., & Francini, G. (2018). Capecitabine plus Oxaliplatin and Bevacizumab followed by Maintenance Treatment with Capecitabine and Bevacizumab for Patients> 75 Years with Metastatic Colorectal Cancer. Clinical Colorectal Cancer.
Piedbois, P., Buyse, M., Rustum, Y., Machover, D., Erlichman, C., Carlson, R., Valone, F., Labianca, R., Doroshow, J., & Petrelli, N. (1992). Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate by the advanced colorectal cancer meta-analysis project. Journal of Clinical Oncology, 10(6), 896-903.
Pluen, A., Boucher, Y., Ramanujan, S., McKee, T. D., Gohongi, T., di Tomaso, E., Brown, E. B., Izumi, Y., Campbell, R. B., & Berk, D. A. (2001). Role of tumor–host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proceedings of the National Academy of Sciences, 98(8), 4628-4633.
Porter, D., Frey, N., Wood, P. A., Weng, Y., & Grupp, S. A. (2018). Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. Journal of hematology & oncology, 11(1), 35.
Raymond, E., Faivre, S., Woynarowski, J. M., & Chaney, S. G. (1998, April). Oxaliplatin: mechanism of action and antineoplastic activity. In Seminars in oncology (Vol. 25, No. 2 Suppl 5, pp. 4-12).
Roder, C., & Thomson, M. J. (2015). Auranofin: repurposing an old drug for a golden new age. Drugs in R&D, 15(1), 13-20.
Rowland, A., Dias, M. M., Wiese, M. D., Kichenadasse, G., McKinnon, R. A., Karapetis, C. S., & Sorich, M. J. (2015). Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. British journal of cancer, 112(12), 1888.
Rustum, Y. M. (1990). Biochemical rationale for the 5-fluorouracil leucovorin combination and update of clinical experience. Journal of Chemotherapy, 2(sup1), 5-11.
Ryuk, J. P., Choi, G.-S., Park, J. S., Kim, H. J., Park, S. Y., Yoon, G. S., Jun, S. H., & Kwon, Y. C. (2014). Predictive factors and the prognosis of recurrence of colorectal cancer within 2 years after curative resection. Annals of surgical treatment and research, 86(3), 143-151.
Sackett, D. L., & Varma, J. K. (1993). Molecular mechanism of colchicine action: Induced local unfolding of. beta.-tubulin. Biochemistry, 32(49), 13560-13565.
Sadahiro, S., Suzuki, T., Ishikawa, K., Nakamura, T., Tanaka, Y., Masuda, T., Mukoyama, S., Yasuda, S., Tajima, T., & Makuuchi, H. (2003). Recurrence patterns after curative resection of colorectal cancer in patients followed for a minimum of ten years. Hepato-gastroenterology, 50(53), 1362-1366.
Saltz, L. B., Cox, J. V., Blanke, C., Rosen, L. S., Fehrenbacher, L., Moore, M. J., Maroun, J. A., Ackland, S. P., Locker, P. K., & Pirotta, N. (2000). Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. New England Journal of Medicine, 343(13), 905-914.
Santana-Davila, R., & Chow, L. Q. (2018). The use of combination immunotherapies as front-line therapy for non-small-cell lung cancer.
Seetharam, R. N., Sood, A., & Goel, S. (2009). Oxaliplatin: pre-clinical perspectives on the mechanisms of action, response and resistance. ecancermedicalscience, 3.
Sharma, A., Kumari, K. M., Manohar, H. D., Bairy, K. L., & Thomas, J. (2015). Pattern of adverse drug reactions due to cancer chemotherapy in a tertiary care hospital in South India. Perspectives in clinical research, 6(2), 109.
Slattery, M. L., Potter, J. D., Ma, K. N., Caan, B. J., Leppert, M., & Samowitz, W. (2000). Western diet, family history of colorectal cancer, NAT2, GSTM-1 and risk of colon cancer. Cancer Causes & Control, 11(1), 1-8.
Stone, J. B., & DeAngelis, L. M. (2016). Cancer-treatment-induced neurotoxicity—focus on newer treatments. Nature reviews Clinical oncology, 13(2), 92.
Strathdee, G., MacKean, M. J., Illand, M., & Brown, R. (1999). A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer. Oncogene, 18(14), 2335.
Sun, W., Sanderson, P. E., & Zheng, W. (2016). Drug combination therapy increases successful drug repositioning. Drug discovery today, 21(7), 1189-1195.
Tan, C., & Du, X. (2012). KRAS mutation testing in metastatic colorectal cancer. World journal of gastroenterology: WJG, 18(37), 5171.
Tanaka, T., Tanaka, M., Tanaka, T., & Ishigamori, R. (2010). Biomarkers for colorectal cancer. International journal of molecular sciences, 11(9), 3209-3225.
Thirion, P., Michiels, S., Pignon, J., Buyse, M., Braud, A., Carlson, R., O'Connell, M., Sargent, P., & Piedbois, P. (2004). Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis.
Tsikitis, V. L., Larson, D. W., Huebner, M., Lohse, C. M., & Thompson, P. A. (2014). Predictors of recurrence free survival for patients with stage II and III colon cancer. BMC cancer, 14(1), 336.
Tsujimoto, H., Tsukioka, S., Ono, S., Sakamoto, E., Sakamoto, K., Tsuta, K., Nakagawa, F., Saito, H., Uchida, J., & Kiniwa, M. (2010). Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase. Oncology letters, 1(6), 973-980.
Vega, P., Valentín, F., & Cubiella, J. (2015). Colorectal cancer diagnosis: pitfalls and opportunities. World journal of gastrointestinal oncology, 7(12), 422.
W. Humphrey, R., M. Brockway-Lunardi, L., T. Bonk, D., Dohoney, K. M., Doroshow, J. H., Meech, S. J., Ratain, M. J., Topalian, S. L., & M. Pardoll, D. (2011). Opportunities and challenges in the development of experimental drug combinations for cancer. Journal of the National Cancer Institute, 103(16), 1222-1226.
Wagstaff, A. J., Ibbotson, T., & Goa, K. L. (2003). Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer. Drugs, 63(2), 217.
Walker, A. S., Johnson, E. K., Maykel, J. A., Stojadinovic, A., Nissan, A., Brucher, B., Champagne, B. J., & Steele, S. R. (2014). Future directions for the early detection of colorectal cancer recurrence. Journal of Cancer, 5(4), 272.
Walko, C. M., & Lindley, C. (2005). Capecitabine: a review. Clinical therapeutics, 27(1), 23-44.
Walsh, J. J., Coughlan, D., Heneghan, N., Gaynor, C., & Bell, A. (2007). A novel artemisinin–quinine hybrid with potent antimalarial activity. Bioorganic & medicinal chemistry letters, 17(13), 3599-3602.
Wang, P. F., Chen, Y., Song, S. Y., Wang, T. J., Ji, W. J., Li, S. W., Liu, N.& Yan, C. X (2017). Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis. Frontiers in pharmacology, 8, 730.
Wang, Y., & Teng, J. S. (2016). Increased multi‑drug resistance and reduced apoptosis in osteosarcoma side population cells are crucial factors for tumor recurrence. Experimental and therapeutic medicine, 12(1), 81-86.
Wiseman, L. R., & Markham, A. (1996). Irinotecan. A review of its pharmacological properties and clinical efficacy in the management of advanced colorectal cancer. Drugs, 52(4), 606-623.
Wu, C. K., Juang, G. D., & Lai, H. C. (2017). Tumor regression and preservation of graft function after combination with anti-PD-1 target therapy without immunosuppressant titration. Annals of Oncology, 28(11), 2895-2896.
Wu, R., Q. Nie, E. E. Tapper, C. R. Jerde, G. S. Dunlap, S. Shrestha, T. A. Elraiyah, S. M. Offer, & R. B. Diasio (2016). Histone H3K27 trimethylation modulates 5-fluorouracil resistance by inhibiting PU. 1 binding to the DPYD promoter. Cancer research, canres-1306.
Xu, L., X. Wu, C. Hu, Z. Zhang, L. Zhang, S. Liang, Y. Xu, & F. Zhang (2016). A meta-analysis of combination therapy versus single-agent therapy in anthracycline-and taxane-pretreated metastatic breast cancer: results from nine randomized Phase III trials. OncoTargets and therapy, 9, 4061.
Yamamoto, N., Honma, M., & Suzuki, H. (2011). Off-target STK10 inhibition by erlotinib enhances lymphocytic activity leading to severe skin disorders. Molecular pharmacology, mol-110.
Yan, Y., & Grothey, A. (2015). Molecular profiling in the treatment of colorectal cancer: focus on regorafenib. OncoTargets and therapy, 8, 2949.
Yokomizo, H., Yoshimatsu, K., Otani, T., Osawa, G., Nakayama, M., Matsumoto, A., Yano, Y., Okayama, S. & Naritaka, Y. (2013). Practical use of capecitabine plus oxaliplatin (CAPEOX) with bevacizumab for patients with metastatic colorectal cancer that cannot expect conversion therapy. Hepato-gastroenterology, 60(128), 1911-1915.
Zhang, L., Pickard, K., Jenei, V., Bullock, M. D., Bruce, A., Mitter, R., G. Kelly, C. Paraskeva, J. Strefford, J. Primrose, G. J. Thomas, G. Packham, & A. H. Mirnezami. (2013). miR-153 supports colorectal cancer progression via pleiotropic effects that enhance invasion and chemotherapeutic resistance. Cancer research, canres-3308.
Zheng, W., Thorne, N., & McKew, J. C. (2013). Phenotypic screens as a renewed approach for drug discovery. Drug discovery today, 18(21-22), 1067-1073.