Antimetabolites for Cancer Treatment

Antimetabolite drugs were among the first effective chemotherapeutic agents discovered. Most of these compounds have similar chemical structures to those of molecules the body uses to create nucleic acid (DNA and RNA). Antimetabolites are chemically similar to compounds needed for normal biochemical activity, but differ enough that they interfere with normal cell function. Generally, antimetabolites induce cell death during the S phase of cell growth when incorporated into RNA and DNA or inhibit enzymes needed for nucleic acid production. These agents are used for a variety of cancer therapies, including leukemia, breast, pancreatic, ovarian, and gastro-intestinal cancers. Antimetabolites is a broad term, and could potentially refer to any drug that interferes with metabolic pathways by inhibiting enzymatic reactions. Antimetabolite medicines used to fight cancer slow the synthesis of biochemicals that cells in the S-Phase use to build new DNA molecules. They are characterized by low molecular weights. Why can’t we just make more chemical compounds that get in the pathway? The problem for drug designers is that metabolic pathways are hard to figure out, and making compounds to interfere with them without causing other problems is fiendishly difficult. Both the pyrimidine bases (uracil, cytosine), and the purine bases (adenine, guanine) are building blocks in the synthesis of DNA and RNA nucleotides. In the replication process, nucleotides combine to form DNA strands. It is less clear how the purine antagonists function, but they may inhibit normal production of DNA.

Pyrimidine Compounds

In 1957 scientists introduced 5-flurouracil (5-FU). 5-FU is a pyrimidine base containing a fluoride atom at the 5 carbon position on the ring. Uracil is a naturally occurring pyrimidine base used in nucleic acid synthesis. It is converted to thymidine by enzyme action. 5-FU is similar in structure to uracil and is converted to two active metabolites (FdUMP and FUTP) that inhibit the activity of the enzyme thymidylate synthetase. The enzyme normally converts uracil to thymidine by adding a methyl group at the fifth carbon of the pyrimidine ring. 5-FU mimics the natural base and functions to inhibit DNA synthesis. The carbon group cannot be added because of the fluoride atom at the five position. Normal DNA synthesis fails. dUTP and FdUTP are incorporated into DNA so that it cannot function normally. In addition, FUTP is incorporated into RNA leading to faulty translation of the RNA. Thus, the synthesis of multiple forms of RNA (messenger, ribosomal, transfer and small nuclear RNAs) is blocked. These combined actions on DNA and RNA are cytotoxic to the rapidly dividing cancer cells. 5-FU is used for the treatment of many malignancies: breast, head and neck, adrenal, pancreatic, gastric, colon, rectal, esophageal, liver, and G-U (bladder, penile, vulva, prostate) . 5-FU may be administered by bolus IV infusion or continuous IV infusion over two days every 2-3 weeks or by oral ingestion. In addition, it may be used to treat skin cancers (basal cell and keratosis) by topical application. Other pyrimidine antagonists include: cytarabine, capecitabine, gemcitabine and decitabine. Cytarabine (aka arabinosylcytosine) is a deoxycytidine base compound that is converted to its active metabolite, ara-CTP. This base is incorporated into DNA and causes strand termination. The cancer cell is unable to divide. This drug has proven effective in acute non-lymphocytic, lymphocytic, myelogenous , and chronic myelocytic leukemias, as well as leptomeningeal carcinomatosis and non-Hodgkin’s lymphoma. Capecitabine is an oral 5-FU pro-drug. It is converted to 5-FU by liver and tumor cells. It is used as adjuvant therapy in colon and breast metastasis. Gemcitabine is an ara-C pro drug which is activated by intracellular phosphorylation. This inhibits DNA and RNA synthesis. It is a first line treatment of pancreatic, metastatic breast, bladder, ovarian and non-small cell lung cancers.

Purine Compounds

There are few clinically useful purine antagonists.  Scientists conjecture that these purine antagonists stop synthesis by decreasing the production of the purine bases or that the antagonist molecules themselves may be incorporated into the DNA strands during synthesis and halt cell replication.  Without adequate amounts of the purine bases, nucleotide production stops and the cancer cell dies. Fludarabine or 2-fluoro-ara-amp is an antimetabolite of the purine class. It functions as a pro-drug. It is dephosphorylated to F-ara-ATP and enters the cancer cell. Upon incorporation into the DNA strand, it halts strand lengthening. The drug has been employed to treat refractory chronic lymphocytic and chronic B cell leukemias, non-Hodgkin’s lymphoma, and T- cell lymphoma. 6-Mercaptopurine (6-MP) is another purine agent used against acute lymphocytic leukemia. It is active in the S phase of cell proliferation. When it is incorporated into DNA and RNA, the nucleic acids are rendered useless. 6-MP may also act through inhibition of de novo synthesis of the purine bases. Genetic mutation may lead to purine resistance. Adenosine deaminase inhibitors are a class of compounds that can be classified under the purine antagonist umbrella.  These include Cladribine and Pentostatin.

Folate Antagonists

An early advancement in cancer research came in the mid-20th Century when pioneering researcher SIdney Farber was able to induce remission in children with leukemia using the antimetabolite drug aminopterin.  In 1953 another milestone was achieved with the first cure of a solid tumor entirely with chemotherapy, the antimetabolite methotrexate.  Folic acid is a necessary compound for the production of nucleotides. It was empirically observed in patients with leukemia that diets low in folate produced lower white cell counts than observed in leukemic patients on normal folate diets. In 1948, a folate antagonist was found effective in childhood leukemia. The antifolate medication methotrexate became an early chemotherapy drug. Between cells folate is converted by the enzyme dihydrofolate reductase (DHFR) to dihydrofolate. This compound is then reduced to tetrahydrofolate (THDF). THDF acts as a carbon carrier compound that donates methyl groups to end target molecules through the enzymatic action of thymidine synthetase. DHFR is continuously used in this process and is the site where the folate antagonists function. The drugs impede enzyme action and hence interfere with nucleotide formation. Methotrexate binds to DHFR reversibly and inactivates it. This prevents methylation and decreases available supplies of purine and thymidine bases for new DNA and RNA synthesis. Methotrexate is active in the S phase of cell growth. It is effective in many methotrexate structuremalignancies. Breast, head and neck, colorectal, non-Hodgkin’s lymphomas, osteosarcoma, bladder and choriocarcinoma are treated with methotrexate. It is also used in acute lymphocytic leukemia, and some types of meningeal carcinomas. Methotrexate is the most common folate antagonist used today even though others have been developed. Drug resistance is a primary complication of treatment with methotrexate. Decreased drug transport into the cell can occur. A lower and less effective dose of methotrexate is observed intracellulary. Genetic mutations and alterations in gene activity may occur as well which alter binding constants to the enzymes or causes increases in the DHFR enzyme within the cell. Pemetrexed is a folate antagonist used in the treatment of mesothelioma and non-small cell lung cancer. Pemetrexed is combined with cisplatin (an agent which promotes DNA cross-linking) to treat those cancers. Pemetrexed acts like methotrexate. It hinders multiple enzymes needed for de novo production of the thymidine and purine nucleotides. Normal DNA and RNA production is prevented. Pralatrexate is also approved for use against cancer, but it is less often used.

Demethylation Agents

Azacitidine and Decitabine work through demethylation. In normal cellular metabolism, cytosine methylation is an epigenetic mark for maintenance of gene silencing across cellular divisions. However, this chemically stable modification may be removed from DNA through demethylation. Azacitidine and Decitabine are chemical analogs of cytidine. Like other antimetabolites they can become incorporated into the nucleic acid.  Once part of the cell’s DNA, it stops methylation by inhibiting DNA methyltransferase and thereby induces cell death. It may also restore normal gene function controlling cell proliferation.

Medicinal Compounds

Azacitidine (aka Azacytidine)

Brand/Trade Names: Vidazaaz Manufacturers: Celgene, Apicore LLC, Archimica, Ash Stevens, Inc., Aspire Lifesciences Pvt Ltd Formula: C8H12N4O5 Mechanism: demethylation. Cytidine analogue. Class: antimetabolite, DNA methyltransferase inhibitor Administration: Oral Notes: Chemical analog of cytidine.  An epigenetic drug.  Approved by the FDA in 2004.  Used for treatment of myelodysplastic syndromes and leukemia.

Capecitabine

Brand/Trade Names: Xeloda Manufacturers: Genentech, Aarti Industries Ltd, Acebright India Pharma Private Limited, Apotex Pharmachem,  Archimica Formula: C15H22FN3O6 Mechanism: antimetabolite Class: Pyrimidine analogue Administration: Oral Notes:  Approved by the FDA in 2005.  Used for treatment of breast cancer and colorectal cancer.

Clofarabine

Brand/Trade Names: Clolar Manufacturers: Sanofi-Aventis US LLC Apicore LLC  Biophore India Pharmaceuticals Pvt Ltd  Emcure Pharmaceuticals  Hangzhou Longshine Bio-Tech Co., Ltd Formula: C10H11ClFN5O3 Mechanism: antimetabolite Class: Purine analogue Administration: Intravenous Notes: Approved by the FDA in 2004.  Used for treatment of acute lymphoblastic leukemia.

Cladribine

Brand/Trade Names: Leustatin, Litak Manufacturers: Reliable Biopharmaceutical Corporation, Ahk Tech, Aspen Biopharma Labs Pvt Ltd, Biophore India Pharmaceuticals Pvt Ltd, Cilag AG Formula: C10H12ClN5O3 Mechanism: antimetabolite, adenosine deaminase inhibitor Class: Purine analogue Administration: Oral Notes:  Approved by the FDA in 1993.  Used for treatment of hairy cell leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and lymphoma.

Cytarabine

Brand/Trade Names: Cytosar-U, Arabinosylcytosine Manufacturers: Pharmacia & Upjohn Company LLC, Ahk Tech, Apotex Pharmachem Inc.,  Archimica,  Asahi Kasei Finechem Formula: C9H13N3O5 Mechanism: antimetabolite Class: Cytosine analogue Administration: Intravenous Notes:  Approved by the FDA in 1992.   Used for treatment of leukemia.

Decitabine

Brand/Trade Names: Dacogen Manufacturers: Otsuka America Pharmaceuticals, Fujifilm Diosynth Biotechnologies Formula: C8H12N4O4 Mechanism: antimetabolite, demethylation Class: Cytosine analogue, DNA methyltransferase inhibitor Administration: Intravenous Notes: Cytidine analog. An epigenetic drug.  Approved by the FDA in 2006.  Used for myelodysplastic syndromes.

Fludarabine

Brand/Trade Names: Fludara Manufacturers: Actavis Pharma Inc, Archimica,   Ash Stevens, Inc.,   Aspen Biopharma Labs Pvt Ltd,  Beijing Lunarsun Pharmaceutical Co. Formula: C10H13FN5O7P Mechanism: antimetabolite Class: Purine analogue Administration: Intravenous Notes: purine analog.  Approved by the FDA in 1991.   Used for chronic lymphocytic leukemia, lymphoma.

Fluorouracil (5F0U)

Brand/Trade Names: Abdrucil, 5-FU Manufacturers: Teva Parenteral Medicines, AMCOL Health and Beauty Solutions, Biotechnica Pharma Global, DCS Pharma AG, DSM Nutritional Products Formula: C4H3FN2O2 Mechanism:  antimetabolite Class: Pyrimidine analogue Administration: Intravenous Notes: Approved by the FDA in 1962.  Used for treatment of bladder, anal, breast, gastrointestinal, thymic, cervical, head and neck, and colorectal cancer

Floxuridine

Brand/Trade Names: FUDR Manufacturers: Zhejiang Hisun Pharmaceutical, ORGANICA Feinchemie GmbH Wolfen, Reliable Biopharmaceutical Corporation   Formula: C9H11FN2O5 Mechanism: antimetabolite Class: Pyrimidine analogue Administration: Intravenous Notes: Chemical analog of pyrimidine.  First approved by the FDA in 1970.  Used for stomach, colon, and kidney cancer.

Gemcitabine

Brand/Trade Names: Gemzar Manufacturers: Evonik Corporation, Arch Pharmalabs, Archimica, Arene Lifesciences Limited, Aspen Biopharma Labs Pvt Ltd Formula: C9H11F2N3O4 Mechanism: antimetabolite Class: Pyrimidine analogue Administration: Intravenous Notes: Approved by the FDA in 1996.  Approved for treatment of sarcoma, pancreatic cancer, ovarian cancer, breast cancer, and non-small cell lung cancer.

Hydroxyurea

Brand/Trade Names: Hydroxycarbamide, Hydrea, Droxia, Mylocel Manufacturers: Qilu Pharmaceutical Co.,  Archimica, Bristol-Myers Squibb, Nishchem International Pvt.,  Olon Spa Formula: CH4N2O2 Mechanism: antimetabolite Class: Administration: Intravenous Notes: Approved by the FDA in 1967.  Used for treatment of chronic myelogenous leukemia, squamous cell carcinoma of the head and neck, melanoma, and ovarian cancer.

Mercaptopurine

Brand/Trade Names: Purinethol, Purixan Manufacturers: Aarti Industries Ltd, Ajinomoto Company,   Changzhou Siyao Pharmaceuticals Co., Fermion Oy, Stason Pharmaceuticals, Inc. Formula: C5H4N4S Mechanism: antimetabolite Class: Purine analogue Administration: Oral Notes: Approved by the FDA in 1953.  Used for treatment of acute lymphoblastic leukemia.

Nelarabine

Brand/Trade Names: Arranon Manufacturers: Novartis Pharmaceuticals Corporation, ALP Pharm Beijing Co.,  Biophore India Pharmaceuticals Pvt Ltd, ChemWerth Inc, F.I.S. Fabbrica Italiana Sintetici SpA Formula: C11H15N5O5 Mechanism: antimetabolite Class: Purine analogue Administration: Intravenous Notes:  Approved by the FDA in 2005.  Used for treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.

Pentostatin

Brand/Trade Names: Nipent Manufacturers: Hospira, Inc Apicore LLC  Biotechnica Pharma Global  ChemPacific Corp Formula: C11H16N4O4 Mechanism: antimetabolite, adenosine deaminase inhibitor Class: Purine analogue Administration: Intravenous Notes: Approved by the FDA in 1991.  Used for hairy cell leukemia.

Thioguanine

Brand/Trade Names: Tabloid Manufacturers: Glaxo Operations UK Limited t/a Glaxo Welcome Operations Formula: C5H5N5S Mechanism: antimetabolite Class: Purine analogue Administration: Oral Notes: Approved by the FDA in 1966.  Used for treatment of acute myeloid leukemia.

Trifluridine/Tipiricil

Brand/Trade Names: Lonsurf Manufacturers: Taiho  Pharmaceuticals  Co Ltd Formula: C5H5N5S Mechanism: antimetabolite Class: Pyrimidine analogue Administration: Oral Notes:  Approved by the FDA in 2015.  Used to treat colorectal cancer and stomach adenocarcinoma.

Antifolates

Pralatrexate

Brand/Trade Names: Folotyn Manufacturers: Allos Therapeutics, Epoch Labs, Haoyuan Chemexpress Co., Hetero Drugs Limited. Mac-Chem Products (India) Pvt. Formula: C23H23N7O5 Mechanism: antimetabolite Class: Antifolate Administration: Intravenous Notes:  Approved by the FDA in 2009.  Used for treatment of lymphoma.

Pemetrexed

Brand/Trade Names: Alimta Manufacturers: Eli Lilly and Company, Acebright India Pharma Private Limited. Arene Lifesciences Limited, Aspire Lifesciences Pvt Ltd, BrightGene Bio-Medical Technology Co. Formula: C20H21N5O6 Mechanism: antimetabolite Class: Antifolate Administration: Intravenous Notes:  Approved by the FDA in 2004.  Used for treatment of mesothelioma and non-small cell lung cancer.

Methotrexate

Brand/Trade Names: MTX, amethopterin Manufacturers: Bedford Labs, Biesterfeld Spezialchemie GmbH, Biovectra Inc, CF Pharma Ltd., Excella GmbH Formula: C20H22N8O5 Mechanism: antimetabolite Class: Antifolate Administration: Intravenous Notes: Approved by the FDA in 1953.  Used by breast cancer, osteosarcoma, leukemia, lung cancer, lymphoma, head and neck cancer, and stomach cancer. methotrexate molecule PDF list of antimetabolites.