Soliciting the Oral Route as a Logical Approach to Managing Colon Cancer

Abstract

According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2018, colon cancer (CC) is the third most common cancer in men and second in women worldwide (Bray et al., 2018). Approximately 1.8 million new colon cancer cases were diagnosed globally in 2018, with nearly 881,000 resulting in deaths (Bray et al., 2018). The exact trigger of CC is still subject to debate but it is generally accepted that predisposing factors include genetics, diet and lifestyle. In any case, the chemical basis for cancer initiation cascade appears to be prompted by byproducts of aerobic metabolism such as reactive oxygen species (ROS). These are known to confer various levels of reactivity to biological tissues which may serve as trigger to cancer development (Finkel, 2011). This has been referred to as oxidative stress and is known to cause damage to lipids, proteins and importantly, DNA. On the other hand, ROS can also regulate other biological processes. It would seem therefore that a good balance in the levels of ROS is necessary within biological systems and any imbalance in this level serves as trigger for cancer. Most CCs develop slowly as polyps and eventually become malignant under uncontrolled growth that begins within the colonic mucosa and then spreads to the rest of the colon layers as a solid tumor. Fortunately, CC can be easily treated if detected early. Treatment and prognosis rely on the depth of the tumor, extent of lymph nodes involvement and metastasis to distant parts of the body (Ong and Schofield, 2016). Chemo- or radiotherapy may be used alone or in combination for long term treatment plans, whilst surgery may be required in severe cases. In radiotherapy, X-ray energy is irradiated to the suspected tumor from a linear accelerator that destroys cellular DNA and thus inhibits cell proliferation (Jong, 2017). On the other hand, chemotherapy relies on use of cytotoxic agents that inhibit cell growth (Wu et al., 2012) and may be administered prior to or after surgery. Chemotherapeutic agents commonly used in the management of CC include 5-fluorouracil (5-FU), irinotecan (CPT-11), leucovorin (l-LV), oxaliplatin (L-OHP), and capecitabine (Van Der Jeught et al., 2018). 5-FU was among the first synthesized anti-cancer drugs, however about 85% of parenterally administered 5-FU dose is metabolized within 15 min into inactive forms (Jordan, 2016). Thus, capecitabine, an orally administrated prodrug of 5-FU, is usually used instead due to the higher tumor response rate, ≈100% bioavailability and lower incidence of side effects (Miura et al., 2017).

The majority of chemotherapeutic drugs are administered intravenously (i.v.), destined to accumulate within tumor regions. However, i.v. administration causes significant distribution in highly perfused organs (e.g., kidney, lung, etc.) compared to tumor sites. This untoward deployment of the i.v. administered chemotherapeutics may impair the functionality of said organs upon long-term exposure (Attili-Qadri et al., 2013; Patel, 2014). Thus, research focused on alternative modes of delivery of therapeutics is warranted. In this regard, soliciting the oral route for delivering anticancer agents in the management of CC seems logical because of the manifestation CC within the gastrointestinal tract (Sharma and Saltz, 2000; Date et al., 2016). Oral administration of therapeutics for CC enables localized deployment at tumor and hence improves its efficacy whilst at the same time reducing systemic toxicity. Furthermore, oral delivery route appropriate for the delivery of anticancer agents destined for the treatment of CC because it reduces stress and discomfort to patients, and offers flexibility in that, they can self-administer the medication and thus forgo hospital visits (Eek et al., 2016). Rectal administration presents a possibility for delivering drugs to the colon however therapy is ineffective if CC is widespread or in the event of local inflammation such as in Inflammatory Bowel Disease (IBD) (Hua, 2014). The unidirectional flow of colonic content is bound to void any device inserted rectally, which may also cause discomfort in patients.