Methotrexate

Indications: Wide spectrum of malignant and non-malignant diseases. Most often for acute leukemia, lymphoma, breast cancer, bladder cancer, squamous cell cancers, and sarcomas(5).
MOA: Folate analogue which inhibits dihydrofolate reductase (DHFR). Folic acid is normally reduced to tetrahydrofolate (THF) by DHFR which an important donor of carbon in purine and thymidine synthesis. 
SE: Nausea, vomiting, diarrhea, stomatitis, myelosuppression, erythema, rash, urticaria, and alopecia. Methotrexate’s 7-OH metabolite may precipitate in renal tubules and can cause renal damage. Can also cause pulmonary toxicity, hepatotoxicity and cirrhosis. Leucovorin can reduce side effects as it is taken up more by normal cells than tumor cells and bypasses DHFR (6).

Leucovorin (folinic acid)

MOA: Acts as a rescue from methotrexate as it does not require dihydrofolate reductase to produce tetrahydrofolate (THF). In contrast to methotrexate, leucovorin enhances effects of    5-Fluorouracil as leucovorin produces more reduced folate which acts as a coenzyme needed for thymidylate synthase inhibition.

6-mercaptopurine (6-MP) and Azathioprine

Indications: Acute lymphocytic and myelogenous leukemia. Small cell non Hodgkin lymphomas(7).
MOA: 6-MP is an analogue of hypoxanthine/guanine and is converted to 6-MP-ribose phosphate (also known as 6-thioinosinic acid (TIMP)) by hypoxanthine-guanine phosphoribosyl transferase (HGPRT). TIMP inhibits purine synthesis and reduces levels of IMP, AMP, GMP. TIMP also converts to thioguanine monophosphate (TGMP) which will incorporate into DNA and RNA and cause cell cycle arrest. Azathioprine is an oral pro drug of 6-MP(6).
SE: Myelosuppression. Anorexia, nausea, vomiting, diarrhea and hepatotoxicity. Azathioprine and 6-MP are metabolized by xanthine oxidase, and thus allopurinol and febuxostat (xanthine oxidase inhibitors) can increase levels of 6-MP and cause myelosuppression.

6-thioguanine

Indications: Acute lymphocytic and myelogenous leukemia.
MOA: Works very similarly to 6-MP. Analogue of hypoxanthine/guanine and is converted to 6-thioguanylic acid (TGMP) by HGPRT. This leads to reduced synthesis of purines and cell cycle arrest when incorporated into DNA(6).
SE: Bone marrow suppression, Long term liver toxicity.

Cladribine

Indications:Hairy cell leukemia
MOA: An analogue of adenosine which terminates DNA replication and also causes DNA strand breaks leading to apoptosis.
SE: Myelosuppression, fever, peripheral neuropathy(7)

Fludarabine

Indications: Chronic lymphocytic leukemia, low grade lymphomas, and acute myeloid leukemia (5). MOA: Is an analogue of adenosine. It inhibits DNA polymerase and terminates DNA and RNA replication(3). SE: Myelosuppression, Neurotoxicity (dose-dependent)(5).

5-Fluorouracil (IV or topical) or Capecitabine (PO)

Indications: Colon, rectum, gastric, pancreas, breast carcinomas and a wide range of other neoplasms in combination with other regimens. Also comes in a topical form for cutaneous neoplasms and disorders(5).
MOA: Fluorinated uracil molecule which forms 5-flurodeoxyuridinemonophosphate (5-FdUMP) which blocks thymidylate synthase which starves cell of thymidine(6). 5-FdUMP acts as a pseudosubstrate and becomes trapped with thymidylate synthase, and the coenzyme n5-n10-methylene tetrahydrofolic acid. Leucovorin drives process further by producing more coenzyme thus further inhibiting thymidylate synthase enzymes. Capecitabine is an oral formulation of 5-FU which is enzymatically converted to 5-FU requiring thymidine phosphorylase. Thymidine phosphorylase activity is concentrated primarily in tumor cells, and thus capecitabine is somewhat tumor specific.
SE: Nausea, vomiting, diarrhea, alopecia, severe ulceration of oral and GI mucosa, bone marrow suppression. Hand foot syndrome or erythematous desquamation is another side effect(6).

Floxuridine (2-deoxy-5-FU)

Indications: Used in palliative treatment of liver metastases of GI adenocarcinoma in liver.
MOA: Analog of 5-FU which is readily turned into 5-FU in the liver.
SE: Nausea, vomiting, diarrhea, stomatitis(6)

Cytarabine

Indications: Acute myelogenous leukemia, acute lymphoblastic lymphoma, and non-Hodgkin lymphoma(7)
MOA: Is a pyrimidine (cytidine) analogue which when incorporated into DNA during replication causes chain termination and inhibits DNA polymerase.
SE: Myelosuppression, neurologic toxicity(5)

Gemcitabine

Indications Pancreatic, ovarian, lung, bladder cancers(7)
MOA: Analogue of nucleoside deoxycytidine which replaces cytosine in DNA synthesis. This leads to inhibited DNA synthesis.
SE: Myelosuppression, nausea, vomiting, alopecia, flu like symptoms, elevated transaminases, proteinuria, hematuria(6).

Hydroxyurea

Indications: Chronic myelogenous leukemia and other myeloproliferative disorders (polycythemia vera, essential thrombocytosis) (5). 
MOA: Blocks DNA synthesis with little effect on RNA synthesis. Inhibits conversion of ribonucleotides to deoxyribonucleotides by blocking ribonucleotide reductase. Specific to S-phase of the cell cycle (7).
SE: Myelosuppression

Dactinomycin (Actinomycin D)

Indications: Wilms tumor, rhabdomyosarcoma, Ewing, Kaposi and other sarcomas(5)
MOA: Intercalates and forms a dactinomycin-DNA complex between guanine and cytosine in DNA. This interferes with DNA dependent RNA polymerase and to a lesser degree DNA synthesis. It also causes single strand DNA breaks.
SE: Bone marrow suppression, nausea, vomiting, diarrhea, stomatitis, alopecia.

Doxorubicin and daunorubicin (CCNS)

Indications: Wide spectrum of cancers most commonly breast, adult sarcomas, pediatric solid tumours, Hodgkin and non-Hodgkin lymphomas and ovarian cancer(5).
MOA: Anthracycline class of chemotherapeutics work in multiple ways including inhibiting topoisomerase II, intercalating DNA and preventing transcription/replication, and generating free radicals which causes oxidative stress. 
SE: Permanent cardiotoxicity and congestive heart failure as a result of free radical formation. Myelosuppression, stomatitis, nausea, vomiting, diarrhea.Note: Dexrazoxane is an inhibitor of iron mediated free radical formation which may protect against anthracycline mediated cardiotoxicity(4).
Note: Dexrazoxane is an inhibitor of iron mediated free radical formation which may protect against anthracycline mediated cardiotoxicity(4).

Bleomycin (G2-M Phase)

Indications: Testicular cancer, lymphomas, local bladder cancer treatment.
MOA: Bleomycin is a combination of copper chelating glycopeptides which cause oxidative damage to DNA which leads to single strand and double strand DNA breaks. It causes cells to arrest in G2 phase and is cell cycle specific.(6)
SE: Pulmonary toxicity (pneumonitis and fibrosis), mucocutaneous reactions like hyperkeratosis, alopecia and blisters may form(4)

Mitomycin C (CCNS)

Indications: Bladder cancer (intravesicle)(7), stomach, pancreas adenocarcinomas, breast and lung cancers(5).
MOA: Is also derived from streptomyces bacteria and has a mechanism similar to the alkylating agents by cross linking DNA.
SE: Myelosuppression, heart, liver, lung, kidney toxicity(4).

Mechlorethamine

Indications: Hodgkins lymphoma, cutaneous T-cell lymphoma(5)
MOA: Alkylates the N7 nitrogen of a guanine in DNA which leads to cross-links between guanines. Halts DNA replication and cause DNA damage.
SE: Myelosuppression, immunosuppression, reactivation of viral infections, CNS related nausea/vomiting (can pre-treat with Ondansetron)(6).

Cyclophosphamide

Indications: Wide variety of cancers. ALL, CLL, Hodgkin and non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, breast, ovary, Wilms tumor, sarcomas (7)
MOA: Prodrug converted to acrolein and phosphoramide mustard which is the active alkylating agent.
SE: Alopecia, nausea, vomiting, diarrhea, myelosuppression, hemorrhagic cystitis/bladder fibrosis as a result of acrolein metabolite. MESNA (sodium 2-mercaptoethane sulfonate) inactivates acrolein reducing this side effect. Also affect germ cells causing testicular atrophy, sterility, amenorrhea. 

Nitrosoureas: Carmustine and Lomustine

Indications: Malignant gliomas, Hodgkin and non-Hodgkin lymphomas(7)
MOA: Major action is its alkylation of DNA at the O6-guanine position. Good penetration of CNS.
SE: Myelosuppression, pulmonary fibrosis, interstitial nephritis(5). 

Busulfan

Indications: High dose prior to bone marrow transplant, Normal doses for CML (5)
MOA: Alkylating agent forming carbonium ions which cause myeloablation 
SE: Myelosuppression, skin changes, pulmonary toxicity and fibrosis

Vincristine (derived from periwinkle – Vinca Alkaloid)

Indications: Indications: Wide spectrum of cancers including Hodgkin and other lymphomas, rhabdomyosarcoma, neuroblastoma, Wilms tumor
MOA: Binds beta-tubulin and block polymerization of microtubules. This stops the cell in metaphase of mitosis.
SE: Neurotoxicity, peripheral neuropathy, myelosuppression(5)

Vinblastine

Indications: Hodgkin and non-Hodgkin lymphoma, breast, bladder, lung, testicular cancer, Kaposi sarcoma, neuroblastoma (7)
MOA: Binds beta-tubulin and block polymerization of microtubules. This stops the cell in metaphase of mitosis.
SE: More myelosuppression than vincristine but lesser level of neurotoxicity.

Paclitaxel and docetaxel

Indications: breast, non small cell lung cancers, ovarian cancers, bladder, head and neck cancer (5)
MOA: Active in G2/M phase. Bind to beta-tubulin and instead of blocking polymerization like vinca alkaloids, taxanes promote and stabilize microtubules which then become non functional.
SE: Hypersensitivity, Neutropenia, peripheral neuropathy

Cisplatin, Carboplatin, Oxaliplatin

Indications: Wide spectrum of cancers including testicular, ovarian, and bladder cancers (5)
MOA: Similar to alkylating agents in that they bind n7-guanine residues causing cross-links which inhibits DNA replication and RNA synthesis. 
SE: Peripheral neuropathy, ototoxicity, nephrotoxicity , nausea, vomiting, myelosuppression. Cisplatin generally causes more nausea, vomiting, and nephrotoxicity than carboplatin; carboplatin associated more often with severe thrombocytopenia than cisplatin.

Irinotecan

Indications: metastatic colon cancer, lung, ovarian, and lymphoma(5)
MOA: Blocks topoisomerase I
SE: Myelosuppression, nausea, vomiting, diarrhea

Etoposide (derived from podophyllum)

Indications: Lung cancers, lymphoma(5)
MOA: Blocks topoisomerase II
SE: Myelosuppression, alopecia, anaphylactic reactions

Selective estrogen receptor modulators (SERMs) have different effects (agonism, partial agonism, antagonism) at estrogen receptors depending on which tissue that estrogen receptor is.

Tamoxifen

Indications: Estrogen responsive breast cancer. Palliative treatment of metastatic breast cancer and as adjuvant therapy after radiation or surgery.
MOA: Competes with estrogen for the hormone binding receptor which is found intracellularly. Produces a nuclear complex which decreases estrogen stimulated DNA synthesis. Acts as an antagonist in breast tissue. Acts as an agonist on estrogen receptors in bone and the endometrium.
SE: Hot flashes, vaginal bleeding, deep vein thrombosis, endometrial hyperplasia and malignancy (6).

Raloxifene

Indications: Risk reduction of breast cancer in those at high risk(6)
MOA: Same mechanism as tamoxifen, except has different tissue effects. Antagonist at breast tissue, partial agonist at bone, and no effect on endometrial tissue.
SE: Hot flashes, deep vein thrombosis (10)

Post menopausal women produce the bulk of their estrogens from the actions of aromatase enzyme which is a target of treatment in estrogen responsive cancers.

Anastrozole, Letrozole

Indications: Estrogen responsive breast cancer in postmenopausal women.
MOA: Estrogen responsive breast cancer in postmenopausal women.
SE: Hot flashes, reduced bone mineral density, arthralgias (9), and dyslipidemia

Exemestane

Indications: Estrogen responsive breast cancer in postmenopausal women
MOA: Irreversible aromatase inhibitor.
SE: Hot flashes, reduced bone mineral density, arthralgias(9)

Leuprolide, Goserelin

Indications: Prostate cancer androgen deprivation therapy, combined therapy with AI in pre-menopausal women with advanced breast cancer
MOA: Analogues of GnRH which stimulate the anterior pituitary. Constant stimulation of the GnRH receptor leads to desensitization of the anterior pituitary.
SE: Initial flare of androgen which then goes down to castration levels. Paired with anti-androgens (ie.flutamide) in initial phase. Impotence, hot flashes, gynecomastia.(9)

Degarelix

Indications: Prostate cancer androgen deprivation therapy
MOA: Antagonist of GnRH receptor which prevents action of GnRH on anterior pituitary.
SE: No initial flare. Impotence, hot flashes, gynecomastia.(9)

Flutamide

Indications: Complete androgen blockade with GnRH agonist/antagonists, or combined with GnRH agonists to block actions of initial flare of testosterone before HPA is desensitized.
MOA: Block androgen receptor interaction with testosterone
SE: Gynecomastia, GI distress, hot flashes(9)

Monoclonal antibodies are derived from cell culture and are directed against a specific antigen. Because of this specificity they generally have less side effects. They can kill cancer cells by blocking cell surface receptors, receptor ligands, or inducing immune cells or activating complement against the antigen-antibody complex(11). Monoclonal antibodies can also be used to deliver chemotherapy, or radionuclides directly to cancer cells thereby preventing exposure of these agents to non cancer cells. They require parenteral administration, and all may have infusion reactions as side effects. Infusion reactions can include fever, chills, nausea, dyspnea, and rashes. Monoclonal antibodies are named with the suffix -mab (11).

Trastuzumab (Herceptin)

Indications: Estrogen responsive breast cancer in postmenopausal women.
MOA: HER-2 is a human epidermal growth factor receptor (a type of cell surface receptor) which activates downstream pathways involved in cancer growth. Trastuzumab is an IgG antibody which selectively blocks HER-2 on tumor cells which overexpress this receptor. This leads to reduced signal transduction as well as antibody-dependent cell mediated cytotoxicity (ADCC) (11).
SE: Cardiotoxicity, reduction in left ventricular ejection fraction, and less commonly heart failure symptoms. Is worsened by prior anthracycline exposure. Generally, trastuzumab cardiotoxicity is reversible on cessation of the drug(12).

Cetuximab (Erbitux)

Indications: Metastatic colorectal cancer, advanced non-small cell lung cancers, metastatic renal cell cancers(5).
MOA: IgG antibody that binds vascular endothelial growth factor (VEGF). This prevents VEGF interaction with receptors on endothelial cell surfaces and inhibits angiogenesis(11).
SE: Bleeding, hypertension, GI perforation(5).

These agents can enter cells and exert their action against intracellular targets of molecular pathways which are amplified in cancer cells. Many of these pathways are mediated by protein kinases. In contrast, traditional chemotherapies target DNA and are less specific for cancer cells. Small molecule targeted agents generally can be administered orally. Small molecule agents end in the suffix -nib. Tyrosine Kinase inhibitors are a prominent example. Other examples include cyclin-dependent kinase inhibitors, and proteasome inhibitors. There are many more small molecule targeted therapies that are beyond the scope of this module.

Imatinib (Gleevac)

Indications: Chronic Myeloid Leukemia, c-kit + GI stromal tumors(5)
MOA: Imatinib is a tyrosine kinase inhibitor active against the constitutively active BCR-ABL fusion protein which arises from the Philadelphia chromosome. The Philadelphia chromosome is involved in the cells of most patients with CML and is a result of the translocation of the long arms of chromosome 9 and 22. If not blocked, CML may progress. Imatinib binds the BCR-ABL protein and locks it into an inhibited state(3).  In addition Imatinib also binds other tyrosine kinases including platelet derived growth factor receptors and c-kit which is involved in GI stromal tumors when constitutively active(3).
SE: Myelosuppression, hepatotoxicity, fluid retention(5)

Gefitinib (Iressa)

Indications: Non small cell lung cancer
MOA: Targets the EGFR tyrosine kinase by competitively blocking ATP required for kinase activity
SE: Diarrhea, papulopustular skin reactions(11)