Table 2.
Clinically FDA-approved drugs targeting nucleotide metabolism in cancer
| Therapeutic agents | Inhibition targets/target pathways | Approved indication | First approved date | References |
|---|---|---|---|---|
| Mercaptopurine | Hypoxanthine–guanine phosphoribosyltransferase, amidophosphoribosyltransferase, Inosine-5'-monophosphate dehydrogenase | Acute lymphatic leukemia | 1953 | [112, 113] |
| Methotrexate | Dihydrofolate reductase, thymidylate synthase, aminoimidazole carboxamide ribonucleotide transformylase, and amido phosphoribosyltransferase | Acute lymphoblastic leukemia, gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, breast cancer, epidermoid cancer of the head and neck, advanced mycosis fungoides, lung cancer, and advanced non-Hodgkin’s lymphoma | 1953 | [114] |
| Fluorouracil | Thymidylate synthase | Colon, esophageal, gastric, rectum, breast, biliary tract, stomach, head and neck, cervical, pancreas and renal cell cancer | 1962 | [108] |
| Thioguanine | DNA | Acute non-lymphocytic leukemias | 1966 | [113, 115] |
| Cytarabine | DNA polymerase | Acute non-lymphocytic leukemia | 1969 | [116] |
| Floxuridine | Thymidylate synthase | Gastrointestinal adenocarcinoma, liver cancer | 1970 | [117, 118] |
| Cisplatin | DNA | Testicular tumors, ovarian tumors and bladder cancer | 1978 | [119] |
| Carboplatin | DNA | Advanced ovarian carcinoma | 1989 | [120] |
| Fludarabine | Ribonucleoside-diphosphate reductase large subunit, DNA polymerase alpha catalytic subunit | Chronic lymphocytic leukemia | 1991 | [121, 122] |
| Cladribine | Ribonucleoside-diphosphate reductase, DNA polymerase | Active hairy cell leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma | 1991 | [123] |
| Pentostatin | Adenosine deaminase | Hairy cell leukemia | 1991 | [29] |
| Hydroxyurea | Ribonucleotide reductase | Acute myeloid leukemia | 1995 | [124] |
| Gemcitabine | Ribonucleoside-diphosphate reductase, thymidylate synthase, UMP-CMP kinase | Ovarian, lung, breast and pancreas cancer | 1996 | [125, 126] |
| Dacarbazine | Unspecific, DNA synthesis | Malignant melanoma, Hodgkin’s disease | 1998 | [127] |
| Capecitabine | Thymidylate synthase | Breast and colon cancer | 1998 | [128] |
| Clofarabine | Ribonucleoside-diphosphate reductase, DNA polymerase | Acute lymphocytic leukemia | 2004 | [129, 130] |
| Azacytidine | Cysteine and methionine metabolism | Chronic myelomonocytic leukemia | 2004 | [131, 132] |
| Nelarabine | Ara-G triphosphate | Acute T-cell lymphoblastic leukemia, T-cell lymphoblastic lymphoma | 2005 | [133] |
| Decitabine | DNA (cytosine-5)-methyltransferase 3A and 3B | Myelodysplastic syndromes (MDS) | 2006 | [134] |
| Oxaliplatin | DNA | Colorectal cancer | 2009 | [120] |
| Idelalisib | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit | Chronic lymphocytic leukemia, follicular B-cell non-Hodgkin lymphoma, and small lymphocytic lymphoma | 2014 | [135, 136] |
| Tipiracil | Thymidine phosphorylase | Colorectal cancer | 2015 | [137] |
| Pemetrexed | Thymidylate synthase, Bifunctional purine biosynthesis protein PURH, Dihydrofolate reductase, Trifunctional purine biosynthetic protein adenosine-3 | Mesothelioma, NSCLC | 2015 | [138] |
NSCLC non-small-cell lung cancer