Anti-cancer agents have various types such as an alkylating agent, a platinum agent, an antimetabolite, an antitumor antibiotic, and an antitumor plant alkaloid. These anti-cancer agents are effective for some cancers but not effective for other cancers. Even when an anti-cancer agent has been confirmed to be effective for a certain cancer, the anti-cancer agent is effective for some patients and not effective for other patients, leading to interindividual differences. Whether or not a cancer of a specific patient has response to an anti-cancer agent is designated as sensitivity to the anti-cancer agent.
Oxaliplatin (L-OHP) is a platinum-based complex anti-cancer agent. Similar to cisplatin (CDDP) and carboplatin (CBDCA), which are other platinum-based complex anti-cancer agents, the action mechanism thereof is thought to be based on inhibition of DNA synthesis or protein synthesis via cross-linking with DNA bases. L-OHP exhibits anti-tumor effect on colorectal cancer, to which CDDP or CBDCA is ineffective, and shows different spectrum of anti-tumor activity from that of a precedent platinum-based complex anti-cancer agent. In the United States of America, L-OHP for use in combination with fluorouracil (5-FU)/levofolinate (LV) was approved as a first line therapy for metastatic colorectal cancer in January, 2004. In Japan, L-OHP was listed in the National Health Insurance price list in the case of combination use thereof with continuous infusional LV and 5-FU (FOLFOX4 regimen) for “advanced/recurrent colorectal cancer not amenable to curative surgical resection” in April, 2005. Until the early 1990's, 5-FU/LV regimen to advanced/recurrent colorectal cancer has provided a survival of 10 to 12 months. In contrast, a FOLFOX regimen combined with L-OHP results in a prolonged survival of 19.5 months (about twice the survival time). In August, 2009, an indication of L-OHP combined with continuous infusional 5-FU/LV to “postoperative adjuvant chemotherapy for colon cancer” was added to efficacy and effectiveness. Thus, L-OHP is a promising drug having an efficacy in an increased number of colorectal cancer patients.
Meanwhile, 5-FU is a fluoro-pyrimidine anti-cancer agent developed in 1957 and even now serves as a basic drug for use in the chemotherapy of gastrointestinal cancer. When incorporated into cancer cells, 5-FU exerts cytotoxic effect through a principle action mechanism of DNA synthesis inhibition induced by inhibition of thymidylate synthase (TS) by an active metabolite, fluorodeoxyuridine-5′-monophosphate (FdUMP), and another mechanism of RNA function inhibition by another active metabolite, 5-fluorouridine triphosphate (FUTP).
Meanwhile, clinical performance including survival rate attained by chemotherapy of advanced or metastatic colorectal cancer has been drastically improved through a combination therapy employing a key drug such as irinotecan (CPT-11) or L-OHP, which was developed in the 1990s, and a fluoro-pyrimidine drug such as 5-FU, which has been a main drug for the therapy of colorectal cancer. However, the response rate of such chemotherapy is as low as about 50%. That is, the chemotherapy is not effective for half of the patients to whom an anti-cancer agent has been administered with high risks such as serious adverse events. Thus, in order to provide an optimum regimen in cancer chemotherapy, there is urgent demand for establishing a marker for predicting the sensitivity of a patient to an anti-cancer agent, which marker enables determination of therapeutic response of individual patients (i.e., indication of a responder or non-responder).
Generally, the therapy schedule of cancer chemotherapy requires a long period of time. After repetition of several courses of chemotherapy while emergence of adverse events is monitored, attainment of a therapeutic effect and continuation of the therapy are assessed. The assessment requires a long period of time and high medical cost, and the adverse events have actually been observed to a certain degree. Thus, if there were means for predicting whether or not individual patients can receive the effect of chemotherapy before or in an early stage of the therapy, the burden of the patients and emergence of adverse events can be reduced or mitigated, leading to reduction in medical cost.
Large-scale prospective clinical trial (FOCUS trial) for investigating biomarkers that predict therapeutic response of advanced colorectal cancer patients to chemotherapy has revealed that only topoisomerase-1 (Topol) exhibits weak relationship with the 5-FU/L-OHP combination therapy as an effect predicting factor (Non-Patent Document 1). This indicates that there has been established no technique that can reliably select a patient who is expected to be effectively treated through the 5-FU/L-OHP combination therapy. Therefore, there is keen demand for establishment of a biomarker that can predict the effect of the FOLFOX regimen employing a triplet combination of L-OHP/5-FU/LV or that can diagnose the therapeutic response to the FOLFOX regimen in an early stage. Also, in recent years, a modified FOLFOX therapy with use of bevacizumab has been established, and new combination therapies employing an antibody drug such as cetuximab or panitumumab, and a low-molecular-weight compound such as irinotecan or dasatinib are now clinically investigated. Therefore, a marker for determining sensitivity of a patient to an anti-cancer agent containing 5-FU and L-OHP, serving as key drugs of these therapies, have been more and more of importance.