RDC Development for Colon Carcinoma

As a leading cause of cancer-related deaths in the world, colon carcinoma, also known as colorectal cancer and colon cancer, as well as bowel cancer and rectal cancer, is one of the most common malignant tumors, ranks third in terms of incidence, and second in the aspect of mortality, according to the statistics from the 2020 global cancer survey. In Industrialized countries, the ratio of the colon to rectum cases is 2:1 or more, while in non-industrialized countries rates are generally the same with increased cancer rates according to industrialization and urbanization. As is shown, colon carcinoma is much more common in high-income countries with increased cancer rates in middle- and low-income countries, whereas colon carcinoma still remains relatively uncommon in Africa and Asia.

Risk Factors of Colon Carcinoma

• Dietary Factors

Diet is definitely the most important exogenous factor so far in the etiology of colorectal cancer, as it can be prevented by appropriate diets and associated factors according to the World Cancer Research Fund. It is reported that red and processed meat, substantial consumption of alcoholic drinks, the body and abdominal fatness are causes of colorectal cancer, while foods containing dietary fiber, and other foods, such as garlic, milk, and calcium, probably protect against colon carcinoma.

• Non-Dietary Factors

Smoking tobacco is positively associated with large colorectal adenomas, a precursor lesion for colorectal cancer, which confirms that exposure to tobacco constituents may be an initiating factor for colorectal carcinogenesis.
Colorectal diseases, including Inflammatory bowel disease and ulcerative colitis, and metabolic syndrome may be two risk factors for colon carcinoma.

• Genetic Factors

Colon carcinoma may be induced by the mutation or loss of FAP, also termed as the adenomatous polyposis coli (APC) gene or germline mutations in six DNA mismatch repair genes.

Traditional Therapies for Colon Carcinoma

Traditional surgical resection, chemotherapy, and radiotherapy are the main treatment options for colon carcinoma, which are not very effective. Therefore, it is crucial to seek highly specific molecular targets expressed on colon carcinoma cells for the treatment of colorectal cancer.

Colon Carcinoma Treatment with RDC

The humanized CC49 monoclonal antibody (HuCC49DCH2), which binds to TAG-72 and inhibits the growth of subcutaneous xenografts, application with ²¹³Bi is the first RDC (Radionuclide Drug Conjugate) utilized in RIT (radio-immunotherapeutic) for colon carcinoma. Trastuzumab, which can target HER-2, is effective in the treatment of disseminated intraperitoneal disease with radiolabeling.

Specificity of the therapeutic efficacy was confirmed in a subsequent experiment with athymic mice bearing LS-174T (human colorectal) intraperitoneal xenografts when injected by an intraperitoneal route. Groups of mice were injected with 500 µCi of ²¹³Bi-HuCC49DCH2, ²¹³Bi-trastuzumab, or ²¹³Bi-human immunoglobulin G (HuIgG), as nonspecific control, or were left untreated. Median survival of 45 days was obtained for the groups of mice that were injected with either ²¹³BiHuCC49DCH2 or ²¹³Bi-trastuzumab compared with 17 days for the mice that were not treated and 28 days for ²¹³Bi-HuIgG injected mice as shown in the Kaplan-Meier survival curves.

Fig.1 Kaplan-Meier survival curves. (Milenic, D. E., et al., 2010, Cancer)

Reference

1. Milenic, D. E., Brady, E. D., Garmestani, K., Albert, P. S., Abdulla, A., & Brechbiel, M. W. (2010). Improved efficacy of α-particle–targeted radiation therapy: Dual targeting of human epidermal growth factor receptor–2 and tumor‐associated glycoprotein 72. Cancer, 116(S4), 1059-1066.