Anti-neoplastic drugs

Anti-neoplastic, anticancer, and chemotherapeutic drugs can be divided into classes based on similar mechanisms of action.

Alkylating agents: They are the most commonly prescribed chemotherapeutic drugs. Alkylating agents act directly on DNA, causing cross-linking of DNA strands, abnormal base pairing, or DNA strand breaks, thus preventing the cell from dividing. Alkylating agents are generally considered to be cell cycle phase nonspecific, meaning that they kill the cell in various and multiple phases of the cell cycle. They are effective at treating slow-growing cancers. They include chlorambucil, cyclophosphamide, thiotepa, ifosfamide, nitrosoureas (carmustine), melphalan, and busulfan. Platinum containing alkylating agents include cisplatin, carboplatin, and oxaliplatin. In addition to DNA damage, platinum containing agents also disrupt cell membrane transport and suppress mitochondrial function.

Antimetabolites: They replace natural substances as building blocks in DNA molecules, thus affecting metabolism and protein synthesis. Antimetabolites are cell cycle specific. They are most effective during the S-phase of cell division because they primarily act upon cells undergoing the synthesis of new DNA for the formation of new cells. The toxicities associated with these drugs are seen in cells that are growing and dividing quickly, like the mucosa of the gastrointestinal tract and bone marrow. Examples of antimetabolites include purine and pyrimidine antagonists such as 5FU (fluorouracil), cytosine arabinoside, and folate antagonists such as methotrexate. Hypomethylating agents such as 5-azacytidine and decitabine act as antimetabolites by affecting cytokine signaling.

5 FU is an inhibitor of thymidylate synthase. Methotrexate (Jylamvo, Otrexup, Rasuvo, Trexall, Xatmep) is an inhibitor of dihydrofolate reductase, which decreases the synthesis of thymidylate and purines and hence inhibits DNA synthesis and protein metabolism. Methotrexate has drug interactions with NSAIDs, amoxicillin, cotrimoxazole, trimethoprim, indapamide, phenytoin, levetiracetam, empagliflozin, theophylline, and omeprazole as these drugs may interfere with the excretion of methotrexate and cause toxicity. Leucovorin (Wellcovorin) is used to treat and prevent methotrexate toxicity, such as bone marrow suppression. Folic acid should be avoided with methotrexate as it makes it less effective to fight cancer cells. Purine antimetabolite mercaptopurine is a prodrug that is activated by the enzyme HGPRT (hypoxanthine guanine phosphoribosyltransferase) to toxic nucleotides. It is inactivated by the enzyme xanthine oxidase. When a xanthine oxidase inhibitor drug like allopurinol (Zyloprim, Aloprim) is used concomitantly, the dose of mercaptopurine needs to be lowered.

Plant alkaloids and antitumor agents: These plant-derived drugs block cell division by binding to microtubule proteins and are most effective during the S and M phases of the cell cycle. They include vinca alkaloids (derived from the periwinkle plant), vincristine, and vinblastine; taxanes including paclitaxel and docetaxel; podophyllotoxins like etoposide and teniposide and camptothecans including irinotecan and topotecan. Podophyllotoxins and camptothecins are also called topoisomerase inhibitors. Topotecan and irinotecan are inhibitors of topoisomerase I. Etoposide and teniposide are inhibitors of topoisomerase II.

Antitumor antibiotics (anthracyclines): They act by binding with DNA, intercalating between base pairs, and preventing RNA synthesis. They cause the uncoiling of DNA strands. Examples are doxorubicin, daunorubicin, mitoxantrone, and bleomycin.

Tyrosine kinase inhibitors: Inhibit enzyme tyrosine kinase (TK) by competing with ATP for binding site on TK. Tyrosine kinases affect cell proliferation and signaling pathways and include growth factor receptors like epidermal growth factor receptor (EGFR) and Insulin receptors. Overexpression of TKs is seen in cancers. Tyrosine kinase inhibitors include imatinib (Glivec), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif), erlotinib (Tarceva), osimertinib (Tagrisso) and alectinib (ALECENSA). Adverse effects include diarrhea, myalgia, congestive cardiac failure, rash, joint pain, and edema. They may activate Hepatitis B and C.

Gonadal hormone antagonists: Hormone sensitive cancers like breast, endometrial, prostate, testicular, and ovarian cancers may respond to hormonal antagonist drugs that inhibit the activity of hormones like estrogen and testosterone on cancer growth and survival. Examples include tamoxifen (Soltamox, Nolvadex), raloxifene (Evista), fulvestrant (Faslodex,) and flutamide (Eulexin). Adverse effects include osteoporosis, pulmonary embolism, hot flashes, stroke, endometrial cancer, gynaecomastia, and liver dysfunction. Another class of drugs that acts similarly are the GnRH or gonadotropin releasing hormone agonists and antagonists. They decrease the levels of sex hormones like estrogens and testosterone by decreasing the levels of regulatory hormones called FSH and LH. Examples include leuprolide (Lupron), goserelin (Zoladex), and degarelix (Firmagon). Adverse effects and uses are similar to other gonadal hormone antagonists.

Aromatase inhibitors: Aromatase inhibitors inhibit the enzyme aromatase that catalyzes the rate-limiting step in estrogen synthesis. They are used to treat advanced breast cancer in postmenopausal women. Examples include letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). Adverse effects include hot flashes, nausea, diarrhea, edema, dyspnea, vaginal dryness, osteoporosis, increased cholesterol, and muscle and joint pains.

Monoclonal antibodies: They are the newest drug class used in the treatment of various cancers. They have specific targets, which are bound by the monoclonal antibody, which helps the immune system recognize and kill the targeted cancer cells. The target proteins are important in cell division and growth. Adverse effects include flu-like symptoms, rash, diarrhea, nausea, vomiting to serious reactions like cardiac failure, circulatory shock, blood clots, and renal dysfunction. The route of administration is intravenous injection. Monoclonal antibody names end with -mab.

Chemotherapeutic drugs are often associated with adverse effects like fatigue, hair loss or alopecia, nausea and vomiting, diarrhea, loss of appetite and low blood counts. Some of the drug specific adverse effects are as follows -

Vinca alkaloids: Peripheral neuropathy, bone marrow suppression, GI upset, alopecia

Taxanes: Peripheral neuropathy, edema, neutropenia, thrombocytopenia, hypersensitivity reactions.

Methotrexate: Mucositis, skin and mucosal ulcers, GI toxicity, hepatotoxicity, pulmonary fibrosis. Prevent toxicity with prophylactic leucovorin/folinic acid

Mercaptopurine: Bone marrow suppression, cholestasis, jaundice

Irinotecan: Diarrhea

Ifosfamide: Hemorrhagic cystitis

Cyclophosphamide: Hemorrhagic cystitis, bone marrow suppression, alopecia, GI upset, SIADH or syndrome of inappropriate antidiuretic hormone secretion , pulmonary and cardiac toxicity. Acrolein is a by-product of cyclophosphamide and ifosfamide. It is a bladder irritant and causes hemorrhagic cystitis. Treatment is by hydration and Mesna (mercaptoethanesulfonate), sold as Mesnex.

5 fluorouracil: GI upset, diarrhea, alopecia

Doxorubicin and daunorubicin: Cardiac toxicity by free radical formation, arrhythmias, cardiomyopathy, CCF. Dexrazoxane protects against cardiotoxicity.

Bleomycin: Pulmonary fibrosis

Cisplatin: Ototoxicity, neurotoxicity, peripheral neuropathy, vomiting, nephrotoxicity, bone marrow suppression. Amifostine or ethyol is an antioxidant that is used to decrease nephrotoxicity caused by cisplatin

Cytarabine: Neurotoxicity, conjunctivitis, keratitis

Procarbazine: Neurotoxicity, peripheral neuropathy, vomiting, myelosuppression, skin reactions and disulfiram-like reaction

Busulfan: Pulmonary fibrosis, adrenal insufficiency, skin pigmentation

Most chemotherapeutic agents may cause a low white blood cell count or neutropenia which predisposes to infections, decreases immunity and may cause bleeding from bone marrow suppression. Filgrastim (Neupogen, Zarxio) is a bone marrow stimulant also known as granulocyte colony stimulating factor or G CSF, that is used to increase white blood cell counts in neutropenia. Sargramostim (Leukine) is also known as granulocyte-macrophage colony stimulating factor or GM CSF and helps to increase white blood cell counts by the bone marrow.

Top selling anticancer drugs and brands: The following anticancer drugs were sold the most - Imatinib (Gleevec), denosumab (Xgeva), pemetrexed (Alimta), trastuzumab (Herceptin), rituximab (Rituxan), bevacizumab (Avastin), atezolizumab (Tecentriq), pertuzumab (Perjeta), osimertinib (Tagrisso) and palbociclib (Ibrance). Most medications on this list are under the group of drugs known as “biologics”.