Vol.:(0123456789) 1 3 Cancer Chemotherapy and Pharmacology https://doi.org/10.1007/s00280-019-03936-w REVIEW ARTICLE Dihydropyrimidine dehydrogenase in the metabolism of the anticancer drugs Vinay Sharma 1  · Sonu Kumar Gupta 1  · Malkhey Verma 1 Received: 3 May 2019 / Accepted: 21 August 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Cancer caused by fundamental defects in cell cycle regulation leads to uncontrolled growth of cells. In spite of the treatment with chemotherapeutic agents of varying nature, multiple resistance mechanisms are identifed in cancer cells. Similarly, numerous variations, which decrease the metabolism of chemotherapeutics agents and thereby increasing the toxicity of anticancer drugs have been identifed. 5-Fluorouracil (5-FU) is an anticancer drug widely used to treat many cancers in the human body. Its broad targeting range is based upon its capacity to act as a uracil analogue, thereby disrupting RNA and DNA synthesis. Dihydropyrimidine dehydrogenase (DPD) is an enzyme majorly involved in the metabolism of pyrimidines in the human body and has the same metabolising efect on 5-FU, a pyrimidine analogue. Multiple mutations in the DPD gene have been linked to 5-FU toxicity and inadequate dosages. DPD inhibitors have also been used to inhibit excessive degradation of 5-FU for meeting appropriate dosage requirements. This article focusses on the role of dihydropyrimidine dehydrogenase in the metabolism of the anticancer drug 5-FU and other associated drugs. Keywords Cancer · Anticancer drugs · Dihydropyrimidine dehydrogenase (DPD) · 5-Fluorouracil (5-FU) · Drug resistance · Drug metabolism Introduction Cancer is the abnormal transformation and proliferation of cells triggered by underlying genetic anomalies. Onco- genic cells grow indefnitely and invade other tissues and organs leading to cancer. Multiple mechanisms of oncogenic activation exist and multiple subtypes of cancers exist [1]. Anticancer drugs are a class of drugs that show efect in combating malignant cancers by either killing or inhibit- ing the growth of such cells. Administration of these anti- cancer drugs is done as single drug therapy or as a mul- tidrug therapy/combination therapy [1, 2]. 5-Fluorouracil is the most commonly used anticancer drug for solid can- cers. Functioning as a pyrimidine analogue, 5-Fluoroura- cil acts as an antimetabolite and disrupts RNA and DNA synthesis, and thereby combats cancerous cells. It is acti- vated inside the cells by multiple enzymes and degraded by Dihydropyrimidine dehydrogenase (DPD) through the pyrimidine degradation pathway. This catabolic activity displayed by the enzyme on 5-FU plays a crucial role in determining its toxicity and efciency towards 5-FU-based cancer therapies. 5‑Fluorouracil Cancer cells divide rapidly by utilising cellular metabolites. Antimetabolites target this characteristic and act by com- peting with normal metabolites for the same targets and displacing them competitively [3]. 5-Fluorouracil (5-FU), one such antimetabolite being used in cancer treatment since 1957, is a heterocyclic aromatic pyrimidine analogue with a Fluorine atom at the C-5 position of Uracil [4]. Also known by its trade name Efudex, or Carac, 5-FU is a key anticancer drug used for broad-spectrum antitumor activity and is commonly used in the chemotherapeutic treatments as a sole remedy for solid tumours such as breast, colorec- tal, lungs, and head and neck cancers [5]. It interferes with DNA synthesis by acting as Uracil analogue and inhibits the essential biosynthesis process such as DNA and RNA * Malkhey Verma malkhey.verma@cup.edu.in; malkhey@yahoo.com 1 Department of Biochemistry and Microbial Sciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab 151001, India