Alkylating Agents
| Common Characteristics of Alkylating Agents |
| Mechanism of Action: Aklylating agents have a chemical structure that contain a bifunctional nitrogen mustard moiety which includes two reactive alkyl groups (hence the term aklylation). These groups can cyclize in an aqueous environment to form a highly electrophilic "immonium ion" that can covalently bind to any nucleophilic compound, including the N-7 nitrogen position on guanine, which therapeutically is a major site of action. Consequently they can produce a cross-linking of DNA when both akyl groups react with pairs of guanine residues in DNA (intrastrand or interstrand). Crosslinking of DNA ultimately results in breaks of the DNA sequence, and cell death. FWIW: these agents can also react chemically with other cellular components containing nucleophilic groups (sulfhydryl, amino, hydroxyl, carboxyl & phosphate groups). Although aklylating agents are not cell cycle specific, rapidly dividing cells are most susceptible to their effects. |
| Drug Resistance: Cancer cells can acquire a resistance to alkylating agents by at least 3 mechanisms including: 1) increased ability to repair DNA lesions; 2) decreased permeability to the alkylating drug; 3) increased production of glutathione or increased glutathione S-transferase which catalyzes the conjugation of the drug to gluathione. |
| Side Effects: myelosuppression, including granulocytopenia, thrombocytopenia, anemia, or a combined loss of formed elements of the blood. Associated increased risk for infections due to decreased host resistance. Nausea & vomiting. Some degree of GI toxicity, reversible hair loss (alopecia). |
| Reference: lecture notes & Katzung's text |
| Drug: Busulfan (Bulsulfex ®) |
| Drug Class: Antineoplastic (Alkylating Agent) |
| Indications: indicated for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia (CML). It has a major degree of specificity for the granulocyte series of cells that are affected in this type of cancer. |
| Side Effects: profound myelosuppression in 100% of patients (& common side effects listed above). |
Pharmacokinetics: typically given intravenously via a central venous catheter as a two hour infusion every 6 hours x 4 consecutive days for a total of 16 doses. All patients should be premedicated with phenytoin as busulfan is known to cross the blood brain barrier and induce seizures. Can be given orally as well. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Cyclophosphamide (Cytoxan, Neosar ®) |
| Drug Class: Antineoplastic (Alkylating Agent) |
| Indications: One of the most widely used alkylating agents. A broad spectrum anticancer drug that can be given alone, but is more commonly given in combination with other drugs (e.g. CHOP, CAF or CMF). Major indications include non-Hodgkin's lymphoma, leukemias, multiple myeloma, breast & ovarian cancer. |
| Side Effects: Hemorrhagic cystitis occurs occasionally (& common side effects listed above). Mensa (Na salt of methylethylsulfonate) can be given to protect the bladder from the toxic effects of cyclophosphamide. |
Pharmacokinetics: Can be given orally (most alkylating agents are given i.v.), and it is well absorbed. Cyclophosphamide in its parent form does not have direct cytotoxic effects. It must be bioactivated by cyt P450 to be effective. cyt P450 metabolism produces 4-hydroxycyclophosphamide (an active metabolite) which spontaneously isomerizes to aldophosphamide (a second active metabolite). Aldophosphamide undergoes non-enzymatic breakdown into both acrolein and phosphoramide mustard which are also cytotoxic. Aldophosphamide can be broken down to an inactive metabolite (carxboxyphosphamide) by aldehyde dehydrogenase (aldehyde oxidase). Aldehyde dehydrogenase can become induced in cancer cells, producing a unique form of drug resistance (see Fig. 55-5 in Katzung). |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Dacarbazine (DTIC ®) |
| Drug Class: Antineoplastic (Alkylating Agent) |
| Indications: Used in combination with other drugs (e.g. ABVD) for Hodgkin's disease. Limited use in non-combination formulation due to severe toxicity. |
| Side Effects: Hepatic necrosis has been reported, photosensitivity. |
Pharmacokinetics: Needs P450 bioactivation to be effective. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Mechlorethamine (Mustargen ®) |
| Drug Class: Antineoplastic (Alkylating Agent) |
| Indications: limited used in combination with other agents (MOPP) for Hodgkin's disease. |
| Side Effects: highly toxic; carcinogenic |
| Reference: www.rxlist.com |
| Drug: Melphalan (Alkeran ®) |
| Drug Class: Antineoplastic (Alkylating Agent) |
| Indications: multiple myeloma |
| Notes: a phenylalanine derivative of nitrogen mustard. |
| Reference: www.rxlist.com |
| Drug: Nitrosoureas (BCNU or Carmustine ®; CCNU or Lomustine ®) |
| Drug Class: Antineoplastic (Alkylating Agent) |
| Indications: Brain tumors & metastases. These drugs are highly lipid soluble & penetrate the blood-brain barrier. |
Pharmacokinetics: All require biotransformation, which occurs by nonenzymatic decomposition to metabolites with both alkylating and carbamoylating activities. |
| Reference: Katzung's text |
Antimetabolites (Structural Analogs)
| Drug: Cytarabine (Ara C ®) |
| Drug Class: Antineoplastic |
| Mechanism of Action: an S phase-specific antimetabolite (of pyrimidine) that is converted to a 5'-mononucleotide (AraCMP), and then to AraCTP, which competitively inhibits DNA polymerase and results in blockade of DNA synthesis. Cytarabine is also incorporated into RNA and DNA. Incorportion into DNA leads to interference with chain elongation and defective fragments of newly synthesized DNA. |
| Indications: limited to treatment of acute myelogenous leukemia (AML), for which it is the major drug. |
| Side Effects: because cytarabine is a bone marrow suppressant, anemia, leukopenia, thrombocytopenia, megaloblastosis, and reduced reticulocytes can be expected |
Pharmacokinetics: Cytarabine is rapidly metabolized and is not effective when taken orally. Because of it's rapid metabolism and S-phase specificity, it must be given either by continuous infusion, or every 8-12 hours for 5-7 days. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: 5-Fluorouracil (Adrucil, Efudex, Fluoroplex ®) |
| Drug Class: Antineoplastic |
| Mechanism of Action: a prodrug that undergoes a complex series of biotransformations to ribosyl and dexoxyribosyl nucleotide metabolites. One of these (FdUMP) forms a covalently bound ternary complex with thymidylate synthase and the reduced folate N5-N10-methylenetetrahydrofolate, a reaction critical for the synthesis of thymidylate. This results in an inhibition of DNA synthesis through a "thymineless death". 5-FU is also converted to FUTP, which is incorporated into RNA, where it interferes with RNA processing & mRNA translation. In addition, 5-FU is converted FdUTP, which can be incorporated into DNA, resulting in inhibition of DNA synthesis & function. Its cytotoxicity is therefore due to effects on both DNA- and RNA-mediated events. |
| Indications: the most widely used agent for colorectal cancer. In addition, it has activity against a wide variety of solid tumors, including those in breast, stomach, pancreas, esophagus, liver, head, neck & anus. |
| Side Effects: nausea, diarrhea, myelosuppression, neurotoxicity |
Pharmacokinetics: . given i.v. & has a short metabolic half-life of ~15 mins. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Methotrexate (Trexall, Methotrex, Rheumatrex ®) |
| Drug Class: Antineoplastic |
| Mechanism of Action: a folic acid antagonist that inhibits dihydrofolate reductase (DHFR), interfering with the synthesis of thymidylate, purine nucleotides & the amino acids serine & methionine, thereby interfering with the formation of DNA, RNA and proteins. Must be bioactivated intracellularly to polyglutamate derivatives, which are selectively retained within cancer cells & have increased inhibitory effects on enzymes involved in folate metabolism, making them important determinants of the duration of action of methotrexate. |
| Indications: acute lymphocytic leukemia (ALL), choriocarcinoma, Burkitt's lymphoma, breast, head & neck tumors. Given either alone or in combination with other drugs. High dose therapy can be effective against osteogenic sarcoma, although you must give a leucovorin "rescue" after high dose therapy to protect bone marrow cells (leucovorin does not penetrate cancer cells as easily). |
| Side Effects: bone marrow suppression, diarrhea, nausea & vomiting, hepatic & renal toxicity. |
| Drug Resistance: tumor cell resistance has been attributed to: 1) decreased cellular uptake (which may be related to incresed activity of P-glycoprotein), 2) decreased polyglutamate formation, 3) synthesis of increased levels of DHFR through gene amplification, and 4) altered DHFR with reduced affinity for methotrexate. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Thioguanine (Tabloid ®) |
| Drug Class: Antineoplastic |
| Mechanism of Action: inhibits several enzymes in the the purine nucleotide pathway (denovo purine biosynthesis), resulting in inhibition of nucleotide interconversion (e.g. IMP --> GMP), resulting in a decrease of intracellular guanine nucleotides, interference in DNA & RNA synthesis. |
| Indications: acute nonlymphocytic leukemias. Thioguanine has a synergistic action with cytarabine in the treatment of adult acute leukemia. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Mercaptopurine (Purinethol ®) |
| Drug Class: Antineoplastic |
| Mechanism of Action: requires intracellular activation, and inhibits a number of enzymes of purine nucleotide interconversion (e.g. IMP --> AMP). This results in an inhibition of DNA & RNA synthesis. |
| Indications: acute lymphocytic leukemia (ALL) & acute myelocytic leukemia (AML) |
| Side Effects: bone marrow suppression, nausea & vomiting |
| Drug Interactions: the dose of mercaptopurine must be reduced to 25% of the usual level when allopurinol is used concomitantly to enhance the elimination of cellular purines that are released following tumor lysis. |
| Notes: |
| Reference: www.rxlist.com & Katzung's text |
Natural Products
| Drug: Bleomycin (Bleo, Bleocin, Blenoxane ®) |
| Drug Class: Antitumor Peptide |
| Mechanism of Action: bleomycin is a small peptide that contains a DNA binding region & an iron-binding domain at opposite ends of the molecule. It acts by intercollating into DNA & reacts with ferous ions (Fe2+) to produce free radicals that cause DNA fragmentation, resulting in single & double strand breaks, and inhibition of DNA biosynthesis. Bleomycin is a cell-cycle specific drug that causes accumulation of cells in the G2 phase of the cell cycle. |
| Indications: Hodgkin's disease , Non-Hodgkin's lymphoma, testicular carcinoma |
| Side Effects: little myelosuppression (unusual for antineoplastics), and as a result it can be combined with other drugs that do produce myelosuppression (e.g. BACOP, ABVD, PEB). Lung toxicity that is dose -limiting, including reversible pneumonitis (8-10%) and, more rarely, a potentially fatal pulmonary fibrosis (1%). |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Actinomycin D or Dactinomycin (Cosmegen ®) |
| Drug Class: Antitumor Antibiotic |
| Mechanism of Action: Dactinomycin intercolates into DNA & inhibits transcription, resulting in cell death. |
| Indications: Wilm's tumor & as an alternative to methotrexate in choriocarcinoma. Its indications are limited due to its toxicity. |
| Side Effects: A highly toxic drug. |
| Reference: www.rxlist.com & Katzung's text |
Anthracycline Antibiotics
| Drug: Daunorubicin or Daunomycin (Daunoxome, Cerubidine ®) |
| Drug Class: Antitumor Antibiotic |
| Mechanism of Action: 1) inhibits topoisomerase II, 2) high affinity binding to DNA through intercalation, resulting in blockade of DNA and RNA synthesis, and DNA strand scission; 3) alterations in cell membrane transport; 4) generation of semiquinone free radicals & oxygen free radicals that cause DNA strand breaks. |
| Indications: acute myelocytic leukemia (AML) "only" |
| Side Effects: dose-limiting myelosuppression & cardiotoxicity |
| Notes: Daunorubicin was the first agent in this class to be isolated, and its current use is limited to the treatment of AML. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Doxorubicin (Adriamycin, Doxil, Rubex ®) |
| Drug Class: Antitumor Antibiotic |
| Mechanism of Action: same as for Daunorubicin (above) |
| Indications: broad spectrum of clinical indications including solid tumors (e.g. breast cancer) and hematoligic malignancies. |
| Side Effects: myelosupression and cardiotoxicity including acute transient ECG changes (reversible) and chronic cardiomyopathy leading to the development of congestive heart failure. The development of CHF is related to the cumulative dose taken over time: ~1% at 450-500 mg/m2; ~11% at 500-600 mg/mm2; ~33% at >600 mg/mm2. |
| Reference: www.rxlist.com & Katzung's text |
Plant Alkaloids
| Drug: Irinotecan (Camptosar ®) |
| Drug Class: Campthothecin Antineoplastic |
| Mechanism of Action: a prodrug that is metabolized by the liver in vivo to a potent inhibitor of topoisomerase I & cause single strand breaks in DNA. (Topoisomerase I is the key enzyme responsible for cutting and religating single DNA strands & inhibition results in DNA damage.) |
| Indications: as first line therapy in metastatic colorectal cancer when used in combination with 5-flurouracil & leucovorin. Used as 2nd line monotherapy in metastatic colorectal cancer who have failed 5-fluorouracil based therapy. |
| Side Effects: myelosuppression, diarrhea, hemorrhagic cystitis, bone marrow suppression, liver function abnormalities |
| Notes: derived from a Chinese tree Camptotheca acuminata |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Topotecan (Hyacamtin ®) |
| Drug Class: Campthothecin Antineoplastic |
| Mechanism of Action: same as for Irinotecan |
| Indications: treatment of patients with advanced ovarian cancer who have failed platinum-based (cisplatin) chemotherapy & 2nd line therapy of small cell lung cancer. |
| Side Effects: similar to irinotecan |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Etoposide (VePesid, Toposar, Etopophos ®) |
| Drug Class: Antineoplastic (Plant Alkaloid) |
| Mechanism of Action: inhibits topoisomerase II, resulting in DNA damage through strand breakage induced by the formation of a ternary complex of the drug, DNA and the enzyme. They block cell division in the late S-G2 phase of the cell cycle. |
| Indications: a 1st line drug when combined with others (PEB) for treatment of testicular tumors & small cell lung cancer. |
| Side Effects: myelosuppression |
| Notes: a semisynthetic derivative of podophyllotoxin (an extract from the mayapple root). |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Paclitaxel (Taxol, Onxol ®) |
| Drug Class: Antineoplastic alkaloid |
| Mechanism of Action: a mitotic spindle poison that binds to microtubules with high affinity & enhances tubulin polymerization. This results in inhibition of mitosis & cell division ("mitotic arrest"). M-phase specific action. |
| Indications: a wide variety of solid tumors including breast, ovarian, bladder, head & neck, small & non-small cell lung cancer. |
| Side Effects: peripheral neuropathy, allopecia, myelosuppression |
| Notes: an alkaloid derived from the Western and European yew. Docetaxel is a semisynthetic analog of paclitaxel, has the same mechanism of action, and is approved for second-line therapy of various cancers with a similar spectrum of indications as paclitaxel. |
| Reference: www.rxlist.com & Katzung's text |
Vinca Alkaloids
| Drug: Vinblastine (Velban ®) |
| Drug Class: Antineoplastic alkaloid |
| Mechanism of Action: binds to microtubule protein in its dimeric form and promotes depolymerization. This results in mitotic arrest at metaphase, and interference with chromosome segregation. |
| Indications: has clinical acitivity against Kaposi's sarcoma, advanced carcinoma of the testis, lymophocytic lymphoma. |
| Side Effects: myelosuppression, nausea & vomiting |
| Notes: isolated from the periwinkle plant |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Vincristine (Oncovin, Vincasar ®) |
| Drug Class: Antineoplastic alkaloid |
| Mechanism of Action: same as vinblastine (above) |
| Indications: wider spectrum of clinical activity than vinblastine. Used with prednisone for acute lymphoblastic leukemia (ALL) in children. Active in combination with other drugs (MOPP, CHOP, BACOP) to treat various hematological malignancies such as Hodgkin's & non-Hodgkin's lymphoma, multiple myeloma. |
| Side Effects: allopecia, peripheral neuropathy. Not as myelosuppressive as vinblastine. (Note: different than for vinblastine). |
| Reference: www.rxlist.com & Katzung's text |
Miscellaneous Agents
| Drug: Cisplatin (Platinol ®) |
| Drug Class: Antineoplastic |
| Mechanism of Action: an inorganic metal complex that kills cells in all stages of the cell cycle, inhibits DNA synthesis, and binds DNA through the formation of interstrand cross-links similar to other alkylating agents. The primary binding site is N7 of guanine, but may form covalent interactions with other nucleotides. Platinum complexes appear to synergize with certain other anticancer drugs (cisplatin is the P in PEB drug combinations). |
| Indications: testicular carcinoma, breast, ovarian & bladder cancer. |
| Side Effects: nephrotoxicity & ototoxicity (therefore don't combine with other drugs with similar toxicities, or in pts with kidney failure). |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Imatinib (Gleevac ®) |
| Drug Class: Antineoplastic "designer drug" |
| Mechanism of Action: an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein. Imatinib prevents the phosphorylation of the kinase substrate by ATP. (see Notes below). |
| Indications: treatment of chronic myelogenous leukemia (CML). |
| Side Effects: hepatotoxicity, edema, fluid retention. tyrosine kinases associated with the platelet-derived growth factor receptor, stem cell factor and c-kit are also inhibited by Imatinib. |
Pharmacokinetics: metabolized by cyt P450 (CYP3A4). |
| Drug Interactions: inhibitors or inducers of the CYP3A4 family. |
| Notes: CML is caused by an abnormal chromosomal translocation that results in the formation of the Bcr-Abl fusion protein. This fusion protein is present in up to 95% of patients with this disease. Hence it is a selective target for drug action against this form of cancer. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Procarbazine (Matulane ®) |
| Drug Class: Antineoplastic |
| Mechanism of Action: inhibits the synthesis of DNA, RNA and protein; produces chromosomal breaks. May alkylate and methylate DNA. |
| Indications: in combination with other anticancer drugs for the treatment of Hodgkin's disease. Procarbazine is a constituent of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen. |
| Side Effects: nausea & vomiting, myelosuppression, peripheral neuropathy, CNS depression. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Trastuzumab (Herceptin ®) |
| Drug Class: Monoclonal Antibody to EGF receptor |
| Mechanism of Action: Trastuzumab is a monoclonal antibody that binds to the extracellular domain of an epidermal growth factor receptor variant (HER2) that is "overexpressed" in some breast cancer cells (see below). Trastuzumab inhibits the proliferation of human tumor cells that overexpress HER2. Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC). In vitro, Trastuzumab-mediated antibody cytotoxicity has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2. |
| Indications: for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease. Trastuzumab in combination with paclitaxel is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have not received chemotherapy for their metastatic disease. Trastuzumab should only be used in patients whose tumors have HER2 protein overexpression. |
| Side Effects: cardiomyopathy - trastuzumab can result in the development of ventricular dysfunction and congestive heart failure. Extreme caution should be exercised in treating patients with pre-existing cardiac dysfunction. |
| Notes: The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. HER2 protein overexpression is observed in 25%—30% of primary breast cancers. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: G-CSF or Filgrastim (Neupogen ®) |
| Drug Class: Recombinant G-CSF |
| Mechanism of Action: G-CSF acts on hematopoietic cells by binding to cell surface receptors. It regulates the production of neutrophils within the bone marrow, and stimulates their proliferation, differentiation, and some cellular functions. |
| Indications: indicated to: 1) decrease the incidence of infection as manifested by febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever; 2) reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with AML. |
| Notes: produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony stimulating factor gene. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Rituximab (Rituxan ®) |
| Drug Class: Monoclonal Antibody |
| Mechanism of Action: a genetically engineered chimeric murine/human monoclonal IgG1 (human Fc) antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The CD20 antigen is expressed on > 90% of B-cell non-Hodgkin's lymphomas. The mechanism of action includes complement-mediated lysis, antibody-dependent cellular cytotoxicity, and induction of apoptosis in the malignant lymphoma cells. This drug appears to be synergistic with chemotherapy for lymphoma. |
| Indications: therapy of patients with relapsed or refractory B cell non-Hodgkin's lymphoma. |
| Notes: CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation, and possibly functions as a calcium ion channel. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Tamoxifen (Nolvadex ®) |
| Drug Class: Antiestrogen |
| Mechanism of Action: a competitive partial agonist-inhibitor of estrogen and binds to the estrogen receptor of estrogen-sensitive tumors. It has a 10 fold lower affinity for ER than does estradiol, indicating the importance of ablation of endogenous estrogen for optimal antiestrogen effect. |
| Indications: Exteremly effective useful for: 1) treament of both early-stage and metastatic breast cancer, 2) as a chemopreventative agent in women at high risk for breast cancer; 3) treatment of endometrial cancer. |
| Side Effects: typically quite mild. Tamoxifen also suppresses serum levels of insulin-like growth factor-1 and up-regulates local production of TGF-beta. |
Pharmacokinetics: given orally & is rapidly absorbed. Half life of 7-14 days. Metabolized by cyt-P450 & its main metabolites also have antitumor activity similar to the parent drug. |
| Reference: www.rxlist.com & Katzung's text |
| Drug: Allopurinol (®) |
| Drug Class: Uricosuric Agent (Adjuvant in Rx of Blood Dyscrasias) |
| Mechanism of Action: Reduces the synthesis of uric acid from purines by inhibiting xanthine oxidase. |
| Indications: An important adjuvant in cancer chemotherapy of blood dyscrasias. Allopurinol treatment should be discontinued when the potential for overproduction of uric acid is no longer present. |
Notes: Treatment of patients with 'blood dyscrasias" such as leukemia, lymphoma and other malignancies with cancer chemotherapy will result in elevated levels of serum purines that are released from "killed" cancer cells. These purines will be converted by xanthine oxidase to uric acid, resulting in potentially massively high blood levels of uric acid, and the development of kindney stones (renal caculi) and other harmful effects if this enzyme isn't inhibited by allopurinol. |
| Reference: www.rxlist.com & Katzung's text |
| Chemical Carcinogenesis |
| (no specific drugs - consult handout) |