Alkylating agents in cancer: Current developments

The term cancer is derived from a Latin word “cancrum” which means crabs, and associated with group of disease which is related with cellular malfunctions. It is one of the major causes of death in developed countries along with heart diseases. Cancer, known as malignant neoplasm consist of irregular cell growth, which forms tumor. Healthy cells divide in controlled manner whereas cancerous cells do not have this ability, therefore replicate and grow out of control resulting in unregulated cell growth and local tissue invasion. Cancer can develop in any organ or tissue at any age. It can be treated if detected at early stage. For treatment of cancer, many options are available which includes chemotherapy, radiotherapy, surgery etc. Alkylating agents have been frontline cancer therapeutics for over sixty years, and their range of applications is still expanding. Functioning by directly damaging DNA, they primarily form covalent cross-links at the N-7 position of guanine bases, which generates double-strand breaks, disrupts accurate base pairing, halts cell proliferation, and eventually triggers apoptosis. However, systemic toxicity and the emergence of resistance, such as enhanced DNA repair via MGMT (O⁶-methylguanine-DNA methyltransferase) or increased detoxification. To overcome these barriers, current strategies emphasize combining alkylators with adjunctive agents, like inhibitors targeting DNA repair enzymes, topoisomerases, COX-2, kinases, phosphatases, multidrug-efflux proteins, and anti-angiogenic drugs to enhance their anticancer potency while minimizing side effects. Here in this review we have discussed the alkylating agent’s history, classification, mode of action, SAR, clinical and preclinical progress, recent development and also natural sources of alkylating agents in cancer therapy.