Colorectal cancer (CRC) is considered the third most common cancer and the fourth most common cause of cancer death worldwide [1,2]. According to the latest annual cancer incidence report in 2015 from the Saudi Cancer Registry, CRC is the first and the third common cancer in men and women, respectively . Although CRC treatment has evolved in recent years, it is ineffective in some patients for many reasons, including change in the absorption, metabolism or drug uptake of the target cells . Another major reason contributing to the failure of the currently used treatment regimen in CRC patients is the development of drug resistance to multiple anticancer agents. Cancer multidrug resistance (MDR) occurs when cancer cells are treated with primary chemotherapy or during recurrence after primary chemotherapy. There are many mechanisms for drug resistance, such as decreasing the uptake of drug, activating the signaling of growth and DNA repair pathways, inducing the anti-apoptotic molecules to inhibit the apoptosis signaling pathways, and increasing the efflux of drug through cellular transporters .
ATP-binding cassette (ABC) transporter genes play an important role in cancer MDR. The family of human ABC transporters consists of 49 members , which are divided into seven subfamilies from A to G . The ABCB subfamily is a subclass of ABC transporters containing 11 members, and among them is ABCB1/MDR1 which has physiological functional sites such as the blood–brain barrier and liver . MDR1 was the first human ABC transporter that was cloned and characterized through its ability to confer MDR phenotype to cancer cells that had developed resistance to chemotherapy drugs .
The MDR1 gene is located on chromosome 7 and encodes P-glycoprotein (Pgp), which is universally accepted as a drug resistance biomarker [5,7]. The MDR1 gene is greatly expressed in many sites, such as the proximal and distal human intestines, and it causes the excretion of several carcinogens from the gut into the intestinal lumen. The excretion increases in drug-resistant tumors that pump out various anticancer drugs . Pgp has an important role in the detoxification system of normal tissues by transporting substrates and protecting the tissues from physiologically active substances, cytotoxic agents, and xenobiotics . The expression of the MDR1 gene and the activity of its product may differ between individuals as a result of genetic polymorphisms. Thus, this condition could change its ability to react with several toxins, carcinogens, and drugs, suggesting its possible association with cancers including CRC [9,10].
When the polymorphisms of genes have the ability to affect the clinical response to chemotherapy, they may affect the absorption, distribution, metabolism, and excretion of drugs . The MDR1 gene has many mutations, and 40 of its SNPs have been described for exon and intron regions and for promoters. Two of the most popularly studied MDR1 gene polymorphisms, (C3435T) and (G2677T), have been found to decrease the expression of Pgp in the intestine . Regarding CRC, many studies found that several MDR1 variants could increase the risk of CRC, including the G2677T and T1236C polymorphisms [8,9,12,13,14,15]. The G2677T SNP of the MDR1 gene is located in exon 21, and it leads to the change from alanine to serine or threonine, which affects the function of Pgp as a pump. SNP T1236C is one of the most common polymorphisms of the MDR1 gene and is located in exon 12, where a silent mutation occurs similar to SNP C3435T . Recently, several studies found that the MDR1 gene polymorphisms contributed to the risk of CRC in several ethnic groups either by changing the structure and function of the pump or by affecting the response of cancer cells to the currently used drugs . CRC chemotherapeutic drugs have evolved in recent years, and they show promising survival rates for CRC patients. Xeliri and Xelox are widely recommended for CRC patients. Xeliri™ is composed of two chemotherapeutic drugs (Xeloda and irinotecan) and is commonly used to treat different cancers, including metastatic CRC. It is usually given to patients in cycles, each one lasting for 2–3 weeks depending on the extent of the disease. Patients usually take Xeloda orally as tablets and irinotecan intravenously . Conversely, Xelox™ is a chemotherapeutic agent comprising Xeloda and Oxaliplatin. It is widely used for bowel cancers including CRC. As in the Xeliri treatment regimen, CRC patients usually take Xeloda orally as tablets and Oxaliplatin intravenously . Both drugs kill cancer cells by exerting their toxic effects that cause DNA damage through different mechanisms. Thus, this study aimed to determine the genotype distribution and allele frequency of two major MDR1 polymorphisms, namely, T1236C and G2677T, in Saudi CRC patients. The genetic results were correlated with the drug response to the major chemotherapeutic drugs (Xeliri and Xelox) used to treat metastatic CRC patients.