5.2.5. Chemotherapy

Chemotherapy for cancer treatment uses drugs (plant-derived or synthetic) called cytostatic drugs (cytotoxic chemotherapy), which aim to stop cancer cells from continuing to divide uncontrollably [55].

It is estimated that 20–30% of newly diagnosed patients with CRC present with unresectable metastatic disease. In addition, a considerable proportion of patients (40–50%) experience disease recurrence after surgical resection or develop metastatic disease, typically in the liver or lungs [56]. To improve the life prognosis of those patients, several drugs have been developed, such as 5-FU, which is considered the gold standard for CRC chemotherapy [56].

5-FU was developed in 1957 by Charles Heidelberger and colleagues at the University of Wisconsin, who observed that tumor tissues preferentially used uracil-type molecules for nucleic acid biosynthesis and postulated that a fluorouracil analog would be easily taken up by cancer cells. Likewise, it would inhibit tumor cell division by blocking the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (thymidylate) [56].

From 1957 to date, 5-FU has been complemented with other adjuvants to improve the overall survival of patients. For instance, Petrelli et al. (1987) found that mixing 5-FU with leucovorin at 500 mg/m<sup>2</sup> in metastatic patients improved overall survival [57]. Goldberg et al. (2004) studied the efficacy in metastatic CRC patients of 5-FU plus leucovorin, irinotecan, and oxaliplatin combinations (FOLFOX) in 795 patients, finding a median survival rate of 19.5 months, which is 35% higher compared with that with other treatments [58], and recently, Magne et al. (2012) investigated the e fficacy of cetuximab with continuous or intermittent 5-FU, leucovorin, and oxaliplatin (Nordic FLOX) treatment versus FLOX alone in the first-line treatment of metastatic CRC, finding an overall survival of up to 20.4 months [59].

Today, there is a growing interest in researching natural drugs as adjuvants for CRC; most of them act against reactive oxygen species (ROS). Reactive oxygen species (ROS) include oxygen molecules, superoxide anion radicals, hydroxyl free radicals, and hydrogen peroxide. ROS are generated in the mitochondrial respiratory pathway. Although an increase in the level of intracellular ROS leads to oxidative stress and DNA damage, the e ffects of ROS are normally balanced by antioxidants, such as reduced glutathione (GSH), ascorbic acid, and uric acid [60]. Disruption of the oxidant–antioxidant balance through alterations to cellular homeostasis or the defective repair of ROS-induced damage is involved in carcinogenesis. Furthermore, it is known that anticancer drugs induce oxidative stress in patients with cancer being treated with chemotherapy [60]. To reduce oxidative stress, investigations are focusing on natural antioxidants. In Table 2, the latest studies for CRC using natural antioxidants are presented. Natural antioxidants are presented as extracts (fruits, plants, and co ffee, among others) or polyphenol fractions from those extracts [61].


**Table 2.** Natural antioxidants for the prevention and treatment of colorectal cancer; recent reports from 2015 to 2019.


### **Table 2.** *Cont.*


**Table 2.** *Cont.*

Accordingly, most of the antioxidants in Table 2 are polyphenols, due to most plant-based food naturally containing them. The basic monomer in polyphenols is a phenolic ring, and generally, these are classified as phenolic acids and phenolic alcohols [61]. Polyphenol consumption is strongly associated with a low cancer risk. For instance, the Mediterranean diet (rich in olive oil polyphenols [91]), reduces the risk of CRC by approximately 4% [92]. However, 4% is still modest; thus, polyphenols are extracted to present higher antioxidant activity and consequentially higher anticancer effects. Moreover, the colorectal anticancer effect can be potentiated if the antioxidant is supplied using a drug delivery system [93].

### **6. Polymer-Based Drug Delivery Systems for Adjuvants for Colorectal Cancer**

Ideally, drugs would target the cancer cells with the exact therapeutic concentration. However, drug delivery is not easily controlled. Drug release rates, cell- and tissue-specific targeting, and drug stability are difficult to predict [93]. Furthermore, when targeting colon cells, the drug may avoid degradation and/or be released early, which would reduce its therapeutic effect.

Likewise, natural and synthetic compounds can be easily degraded by air, UV light, and moisture, and lose their antioxidant potential [94]. Thus, encapsulation is important for improving their stability and, overall, generating long-term desorption profiles that improve the CRC adjuvant treatments.
