Cancer Drugs
DNA methyltransferase (DNMT) Fact:
-A family of enzymes that catalyze the transfer of a methyl group to DNA. -Three active DNMTs have been identified in mammals: DNMT1, DNMT3A, and DNMT3B -*DNMT is often found highly active to silence the tumor suppressor genes in cancer.*
CHOP
-Cyclophosphamide, hydroxydaunorubicin, Oncovin (trade name for vincristine), prednisone -Combination Therapy Example Remember the goal: Maximize cell killing efficacy, minimize resistance, minimize toxicity to patient!!!
mTOR Complexes Fact
-Two multiprotein complexes (mTORCs): mTORC-1 and mTORC-2. -*mTORC-1 is rapamycin-sensitive; mTORC-2 is rapamycin-insensitive.*
Timeline for cancer chemotherapy
1. Intermittent Dosing - Often given in large doses intermittently (every 2-3 weeks) rather than small doses continuously. * Allows partial recovery of normal cells (for example, bone marrow). But also time for cancer cell regrowth and development of resistance * May give time for non-dividing cells to leave G0 thus making them more susceptible to subsequent chemotherapy 2. Some cancers are treated continuously. - Slow cycling (multiple myeloma)
Rationale for combination therapy
1. To reach the maximal cell kill 2. Choose drugs with *single agent activity* against the cancer 3. Choose drugs with *different mechanisms* to -Affect heterogeneous population of malignant cells -Increase effectiveness and to decrease resistance to therapy 4. Choose drugs with *non-overlapping toxicities* to increase tolerability of therapy 5. Choose drugs are *synergistic* with each other 6. Choose drugs can be given in its *full dosage.* 7. Add *adjuvants* to treat adverse effects
Cancer therapy limitations
1. Toxicity - Many drugs have dose-limiting toxicity 2. "Total cell kill" - Chemotherapy generally follows first-order kinetics (Solid Tumors grow to about 1 cm in diameter or ~1 x 109 cells in the primary tumor site before it is evident clinically. Often, tumors can have over 1012 cells. A constant fraction of cells are killed with each dose *making it difficult to achieve total cell kill* (killing 99.99% of a tumor with 1012 cells still leaves 108 malignant cells). 3. Resistance 4. Tumor progression - Development of heterogeneity of malignant cells
Melphalan Class: Mechanism of action: Administration: Toxicity: Clinical applications:
Class: Cancer Drug; Alkylating agents; Nitrogen mustard analogue Mechanism of action (MOA): - Trade name: Alkeran - An alkylating agent attaches the alkyl group to the *N7 position of guanine.* It cross links DNA and RNA. Administration: Oral or I.V. administration. Toxicity: 1) Nausea and vomiting, and mucositis 2) Myelosuppression (bone marrow suppression), including: - Decreased white blood cell count causing increased risk of infection - Decreased platelet count causing increased risk of bleeding - Can cause a secondary malignancy (e.g. leukemia) Clinical applications: Multiple myeloma, breast cancer, ovarian cancer
Cyclophosphamide Class: Mechanism of Action: Administration: Bioactivation pathway: Toxicity: Clinical Applications:
Class: Cancer Drug; Alkylating agents; Nitrogen mustard analogue Mechanism of Action: -One of the most widely used alkylating agents. -Bis-alkylate the DNA, inducing crosslinks in the DNA-intrastrand and interstrand crosslinks. Administration: Can be administered via the oral (High oral bioavailability) and I.V. routes with equal clinical efficacy. Bioactivation pathway: -Is inactive in its parent form -Must be activated to cytotoxic forms by liver microsomal enzymes. -The cytochrome *P450 mixed-function oxidase system* converts cyclophosphamide to active metabolites (*4-hydroxycyclophosphamide*, which is in equilibrium with aldophosphamide). These metabolites are delivered to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—*phosphoramide mustard* and acrolein—occurs. Toxicity: 1) General toxicity: Nausea and vomiting 2) Unique toxicity: - Its metabolite, acrolein, can cause severe cystitis, *fancoli-like syndrome in kidneys.* - CNS toxicity manifest by confusion, drowsiness, hallucinations. Clinical applications: Cancer (only 1st one): *Breast cancer*, ovarian cancer, non-Hodgkin's lymphoma, CLL, soft tissue sarcoma, neuroblastoma, Wilms' tumor, rhabdomyosarcoma Autoimmune diseases: severe rheumatoid arthritis, multiple sclerosis
Cisplatin Class: Fact: MOA: Administration: Elimination: Toxicity: Clinical Applications:
Class: Cancer Drug; Alkylating-like agents; Platinum compound Fact: Cisplatin (cis-diamminedichloroplatinum II, CDDP) is an inorganic metal complex. Mechanism of action: -*Exert cytotoxic effects in the same manner as alkylating agents.* -Kill tumor cells in all stages of the cell cycle and bind DNA through the *formation of intrastrand and interstrand cross-links*, leading to *inhibition of DNA synthesis and function.* -The primary binding site is the *N7 position of guanine.* Administration: I.V. administration. The patient is typically given saline solution intraveneously before, during and after the drug is injected and advised to maintain adequate water consumption for a day. Elimination: Extensively cleared by the kidneys and excreted in the urine. Dose modification is required in patients with renal dysfunction. Toxicity: Acute toxicity: Nausea and vomiting Delayed toxicity: *Nephrotoxicity*, peripheral sensory neuropathy, ototoxicity, nerve dysfunction Clinical applications: A *broad range of solid tumors*, including non-small cell and small cell lung cancer, breast cancer, bladder cancer, cholangiocarcinoma, gastroesophageal cancer, head and neck cancer, ovarian cancer, germ cell cancer
Carboplatin Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Alkylating-like agents; Platinum compound Fact: A *second-generation platinum analog*. Mechanisms of cytotoxic action, mechanisms of resistance, and clinical pharmacology are identical to those described for cisplatin. MOA: same as common MOA Administration: -Vigorous intravenous hydration *is not* required for carboplatin therapy -Viewed as an easier agent to administer to patients. -*Has replaced cisplatin in various combination chemotherapy regimens.* Toxicity: Acute toxicity: Nausea and vomiting Delayed toxicity: 1) *Myelosuppression*; rarely peripheral neuropathy, renal toxicity, hepatic dysfunction 2) In contrast to cisplatin, it *exhibits significantly less renal toxicity and gastrointestinal toxicity.* Clinical Applications: 1) Has broad-spectrum activity against *a wide range of solid tumors*, including non-small cell and small cell lung cancer, breast cancer, bladder cancer, head and neck cancer, ovarian cancer 2) Widely used in transplant regimens to treat *refractory hematologic-malignancies.*
Methotrexate (MTX) Class: Mechanism of Action: Administration: Elimination: Toxicity: Distinctive Adverse Effects: Clinical Uses:
Class: Cancer Drug; Antimetabolite, Folate Analog Mechanism of Action: MTX is a folic acid (folate) analog; Binds to the active catalytic site of *dihydrofolate reductase (DHFR)* and inhibits its activity; Inhibits the synthesis of tetrahydrofolate (THF); THF is the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate (transformation of dUMP to dTMP). MTX undergoes conversion to series of *polyglutamates (MTX-PGs)* (with the addition of up to 5-7 glutamate residues). - Formation of MTX-PG is critically important for the therapeutic action of MTX. - PGs process is catalyzed by the enzyme folylpolyglutamate synthase *(FPGS)*. - Adding PGs prevents MTX egressing the cell. - MTX-PGs display increased inhibitory effect for thymidylate synthethase (TS) Administration: Intravenous (I.V.), intrathecal, or oral route. Oral bioavailability is saturable and erratic at doses greater than 25 mg/m2. Elimination: Renal excretion is the main route of elimination. Dose modification is required in the setting of renal dysfunction. Care must also be taken when used in the presence of drugs such as aspirin, nonsteroidal anti-inflammatory agents, penicillin, and cephalosporins, as these agents inhibit the renal excretion of MTX. Toxicity (just know first 2): Mucositis, diarrhea, myelosuppression with neutropenia and thrombocytopenia, GI epithelial damage, alopecia, defective oogenesis or spermatogenesis Distinctive adverse effect: Nephrotoxicity (encourage adequate hydration to prevent crystallization in renal tubules), teratogenic Clinical applications: 1) Cancers: Breast cancer, head and neck cancer, osteogenic sarcoma, primary central nervous system lymphoma, non-Hodgkin's lymphoma, bladder cancer, choriocarcinoma 2) Non-cancers: Rheumatoid arthritis, psoriasis
6-mercaptopurine (6-MP; purinethol) Class: Mechanism of Action: Mechanism of Resistance: Administration and Elimination: Toxicity: Clinical Applications:
Class: Cancer Drug; Antimetabolite; Purine analog Mechanism of Action: -Functions as analog of the natural purines hypoxanthine (H). -Is catalyzed by hypoxanthine-guanine phosphoribosyltransferase (*HGPRT*) yielding 6-MP riboside -5'phosphate or T-IMP, which can be incorporated into DNA. -*T-IMP leads to inhibition of glutamine-5-phosphoribosylpyrophosphate (PRPP) amidotransferase (first step in de novo synthesis). Most important effect for 6-MP.* Mechanism of Resistance: *Deficiency or lack of HGPRT*; Decreased drug transport; alteration in inhibition of PRPP amidotransferase. Administration and elimination: Available in both oral and intravenous forms, but oral bioavailability only 10%-50% due to first-pass metabolism by xanthine oxidase in the liver. Elimination of 6-MP is hepatic. Toxicity: myelosuppression and hepatotoxicity Clinical Applications: Acute myelogenous leukemia (AML)
Capecitabine Class: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Antimetabolite; Pyrimidine Analog MOA: -*oral prodrug of 5-FU.* -Undergoes extensive metabolism in the liver to convert into 5-FU. -The expression of *thymidine phosphorylase* has been shown to be significantly higher in solid tumors than in normal tissue, particularly in breast cancer and colorectal cancer. Administration: Oral administration, with 70-80% oral bioavailability. Toxicity: Hand-foot syndrome, diarrhea, myelosuppression, nausea and vomiting Clinical applications (only focus on 1st 2): *Breast cancer, colorectal cancer*, gastroesophageal cancer, hepatocellular cancer, pancreatic cancer
5-fluorouracil (5-FU) Class: MOA: Administration and Elimination: Toxicity: Clinical Applications:
Class: Cancer Drug; Antimetabolite; Pyrimidine Analog Mechanism of Action: *-Inhibits thymidylate synthase (TS) (conversion of dUMP to dTMP), leading to thymidine depletion.* -Enhances the incorporation of FdUTP into DNA, resulting in inhibition of DNA synthesis and function. -Enhances incorporation of FUTP into RNA resulting in alteration in RNA processing. Administration and elimination: - I.V. administration. - Extensively *metabolized by the liver, by dihydropyrimidine dehydrogenase (DPD).* Toxicity: - Nausea, mucositis, diarrhea, bone marrow depression, neurotoxicity -Toxicity is enhanced with leucovorin because 5dUMP binds tightly to TS in the presence of leucovorin. -Can cause significant mucositis and diarrhea particularly if deficient in dihydropyrimidine dehydrogenase (DPD). -Overdose rescue with thymidine *-Photosensitivity* *-Potent radiosensitizer* -Skin hyperpigmentation and rashes are common. These may be lessened with daily administration of pyridoxine (Vitamin B6). Clinical applications: Colorectal cancer, anal cancer, breast cancer, gastroesophageal cancer, head and neck cancer, hepatocellular cancer
Gemcitabine (GEMZAR) Class: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Antimetabolite; Pyrimidine analog Mechanisms of action: *DUAL Mechanisms* -A deoxycytidine analog that *inhibits ribonucleotide reductase (RNR)* activity (conversion of UDP-dUDP and CDP-dCDP), so that inducing a depletion of cellular pool of deoxynucleotides (dNTP). *-Inhibits incorporation of dCTP into DNA* by DNA polymerase Additional MOA info: -The active form is gemcitabine diphosphate (2',2'-difluoro-2'-deoxycytidine diphosphate, *dFdCDP*) and gemcitabine triphosphate (*dFdCTP*) converted inside cells. -*dFdCTP*-mediated inhibition of dCMP deaminase is responsible for the prolonged cellular half-life of the active dFdCTP. Therefore, increases effectiveness! Administration: I.V. administration only. Toxicity: Nausea, vomiting, diarrhea, myelosuppression, flu like syndrome, pulmonary toxicity, causes more thrombocytopenia than neutropenia, a potent radiosensitizer Clinical applications: Pancreatic cancer, bladder cancer, breast cancer, non-small cell lung cancer, ovarian cancer, non-Hodgkin's lymphoma, soft tissue sarcoma
Ara-C (cytarabine or cytosine arabinoside) Class: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Antimetabolite; Pyrimidine analog Mechanisms of actions (MOA): -Activated by kinases to Ara-CTP (cytarabine triphosphate). *-MOA is similar to Gemcitabine:* *-Inhibits ribonucleotide reductase (RNR)* activity (conversion of UDP-dUDP and CDP-dCDP). *-Inhibits incorporation of dCTP into DNA* by DNA polymerase Administration: - I.V. administration because of high levels of cytidine deaminase in GI musosa. -Ara-C must be phosphorylated to triphosphate form for activity. Toxicity: Fever, hand-foot syndrome, myelosuppression with neutropenia and thrombocytopenia, nausea and vomiting, cerebellar ataxia Clinical Applications: AML, ALL, CML in blast crisis *Ara-C is the most important antimetabolite used in AML therapy.*
Hydroxyurea (HU) Class: MOA: Administration and elimination: Toxicity: Clinical Applications:
Class: Cancer Drug; Antimetabolite; pyrimidine analog Mechanism of Action: Inhibition of ribonucleotide reductase (RNR). Administration and elimination: Oral administration, oral bioavailability 80%-100%. Renal excretion. Consideration should be given to decreasing the dosage of HU in patients with renal impairment. Toxicity: drowsiness, nausea, vomiting and diarrhea, constipation, mucositis, anorexia, stomatitis, bone marrow toxicity, alopecia (hair loss), skin changes, abnormal liver enzymes, creatinine and blood urea nitrogen. Clinical applications: 1) Cancer: Chronic myelogenous leukemia (largely replaced by imatinib, but still in use for its cost-effectiveness), melanomas 2) Non Cancer: Sickle-cell disease (breaks down cells that are prone to sickle, as well as increasing fetal hemoglobin content)
Doxorubicin Class: MOA: Administration: Metabolism and elimination: Toxicity: Clinical Applications:
Class: Cancer Drug; Cytotoxic Antibiotics; Anthracyclines MOA: Same as common MOA of Anthracyclines Administration: - Administered via the I.V route. - Generally used in combination with other anticancer agents (eg, cyclophosphamide, cisplatin, and 5-FU), and clinical activity is improved with combination regimens as opposed to single-agent therapy. Metabolism and elimination: -Metabolized to doxorubicinol in the liver; and dose reduction is required in the setting of liver dysfunction. -Renal excretion of drug and its metabolites occurs within 6 hours and the *urine may turn bright red* in color. -Near 50% of drug is eliminated in the feces via biliary excretion. Toxicity: Acute toxicity: Pericarditis-myocarditis syndrome, nausea, red urine (not hematuria) Delayed toxicity: *Cardiotoxicity*, alopecia, myelosuppression, stomatitis Clinical applications: Breast cancer, Hodgkin's and non-Hodgkin's lymphoma, soft tissue sarcoma, ovarian cancer, non-small cell and small cell lung cancer, thyroid cancer, Wilms' tumor, neuroblastoma
Daunorubicin Class: MOA: Administration: Metabolism and elimination: Toxicity: Clinical Applications:
Class: Cancer Drug; Cytotoxic Antibiotics; Anthracyclines MOA: Same as common MOA of Anthracyclines Administration: I.V route. Metabolism and elimination: Same as Doxorubicin Toxicity: Acute toxicity: Pericarditis-myocarditis syndrome, nausea, fever, red urine (not hematuria). Delayed toxicity: *Cardiotoxicity*, alopecia, myelosuppression Clinical applications: -In contrast to doxorubicin, its efficacy in solid tumors is limited. -Mainly used to treat: *AML, ALL*
Bleomycin Class: MOA: Administration: Elimination: Toxicity: Clinical Applications:
Class: Cancer Drug; Cytotoxic Antibiotics; Antitumor Antibiotics MOA: -A *glycopeptide* antibiotic produced by the bacterium Streptomyces verticillus. -Contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule. -Binds to DNA, resulting in *single- and double-strand breaks* due to oxidation of a DNA-bleomycin-Fe(II) complex by free radical formation. -A *cell cycle-specific* drug that causes accumulation of cells in the G2 phase of the cell cycle. (G2-M phase) Administration: Can be given subcutaneously, intramuscularly, or intravenously. Elimination: Mainly via renal excretion, and dose modification is recommended in patients with renal dysfunction. Toxicity: Acute toxicity: Allergic reactions, fever, hypotension Delayed toxicity: pulmonary fibrosis, skin toxicity, mucositis, alopecia, *Raynaud's phenomenon* Comments: 1) Toxicity may be due to low expression of bleomycin hydrolase in the lung and skin. 2) Rarely causes myelosuppression. Clinical applications: Hodgkin's and non-Hodgkin's lymphomas, germ cell tumor, head and neck cancer, and squamous cell cancer of the skin, cervix, and vulva.
Dactinomycin Class: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Cytotoxic Antibiotics; Antitumor Antibiotics MOA: -A *polypeptide antibiotic* isolated from soil bacteria of the genus Streptomyces -Inhibits transcription by *binding DNA* at the transcription initiation complex and *preventing elongation of RNA chain by RNA polymerase.* -May be metabolized to produce a free-radical generating species which *may produce some DNA single-strand breaks.* Administration: Dactinomycin is a clear, yellow liquid. I.V. administration. Toxicity: *Myelosuppression*, fatigue, hair loss, mouth ulcer, loss of appetite and diarrhea. Clinical applications: Wilms' tumor, Ewings' sarcoma, rhabdomyosarcoma, gestational trophoblastic neoplasia, malignant hydatidiform mole
Docetaxel Class: Fact: MOA: Metabolism and Excretion Toxicity: Clinical Applications:
Class: Cancer Drug; Microtubule Inhibitors; Taxanes Fact: A semisynthetic taxane derived from the European yew tree. Mechanism of action (MOA): Same as paclitaxel. Metabolism and excretion: Same as paclitaxel. Toxicity: Acute toxicity: Hypersensitivity Delayed toxicity: *Neurotoxicity* (myalgia/arthralgia, hand-foot syndrome), hand-foot syndrome, fluid retention, myelosuppression with neutropenia Clinical applications: *Breast cancer*, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, bladder cancer
Paclitaxel (Taxol) Class: Fact: MOA: Metabolism and Excretion: Toxicity: Comments: Clinical Applications:
Class: Cancer Drug; Microtubule Inhibitors; Taxanes Fact: An alkaloid ester derived from the Pacific yew (Taxus brevifolia). Mechanism of action (MOA): -Functions as a mitotic spindle poison through binding to microtubules with *enhancement of tubulin polymerization.* -Results in inhibition of mitosis and cell division. Metabolism and excretion: -Metabolized extensively by the liver *P450 system.* -Nearly 80% of the drug is excreted in feces via the *hepatobiliary route.* Dose reduction is required in patients with liver dysfunction. Toxicity: Acute toxicity: Nausea, vomiting, hypotension, arrhythmias, *hypersensitivity* Delayed toxicity: *Peripheral sensory neuropathy, myalgia (muscle pain)/arthalgia (joint pain), hand-foot syndrome*, myelosuppression Comments: Hypersensitivity reactions may be observed in up to 5% of patients, but the incidence is significantly reduced by premedication with dexamethasone, diphenhydramine, and an H2 blocker. Clinical applications: A broad range of solid tumors, including *breast cancer*, non-small cell and small cell lung cancer, ovarian cancer, gastroesophageal cancer, prostate cancer, bladder cancer, head and neck cancer
Vincristine Class: Fact: MOA: Metabolism: Excretion: Toxicity: Clinical Applications:
Class: Cancer Drug; Microtubule Inhibitors; Vinca alkaloids Fact: An alkaloid derived from the periwinkle plant Vinca rosea. Mechanism of action (MOA): -Inhibition of tubulin polymerization by *disrupting assembly of microtubules* (an important part of the cytoskeleton and the mitotic spindle) -Causes *mitotic arrest in metaphase (M phase)*, brings cell division to a halt, then leads to cell death. Metabolism: Metabolized by the liver P450 system. Excretion: The majority of the drug is excreted in feces via the hepatobiliary system. Dose modification is required in the setting of liver dysfunction. Toxicity: Acute toxicity: None Delayed toxicity: *Neurotoxicity with peripheral neuropathy*, *vesicant*, paralytic ileus, myelosuppression, alopecia, SIADH (syndrome of inappropriate secretion of antidiuretic hormone). Clinical applications: ALL, Hodgkin's and non-Hodgkin's lymphoma, rhabdomyosarcoma, neuroblastoma, Wilms' tumor
Vinblastine Class: Fact: MOA: Metabolism: Excretion: Toxicity: Clinical Applications:
Class: Cancer Drug; Microtubule Inhibitors; Vinca alkaloids Fact: An alkaloid derived from the periwinkle plant Vinca rosea. Closely related in structure to Vincristine. Mechanism of action (MOA): Same as Vincristine. Metabolism: Same as Vincristine. Excretion: Same as Vincristine. Toxicity: Acute toxicity: nausea and vomiting Delayed toxicity: Neurotoxicity, vesicant, *myelosuppression*, mucositis, alopecia, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), vascular events. Clinical applications: Hodgkin's and non-Hodgkin's lymphoma, germ cell cancer, breast cancer, Kaposi's sarcoma
Azacitidine (5-azacytidine) Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Chemical Inhibitor; Epigenetic Pathway inhibitor; DNMT Inhibitor Fact: A chemical analogue of cytidine (C), a nucleoside present in DNA and RNA. Mechanism of action (MOA): -*Covalently binds between the C6 atom of the cytosine (C) and the DNMTs, inhibiting DNMTs.* -Triggers *DNA damage* signaling, resulting in the degradation of trapped DNMTs. -Leading to loss of methylation marks of DNA (hypomethylation of DNA). -Also, incorporates into RNA, leading to the dissembly of polyribosomes, and *inhibition of the production of protein.* Administration: I.V. infusion or injection under the skin Toxicity: Myelosuppression, GI (diarrhea, constipation), skin (pale skin, easy bruising or bleeding) Clinical applications: myelodysplastic syndrome (MDS) (a type of cancer in which the bone marrow does not make enough healthy blood cells and there are abnormal (blast) cells in the blood and/or bone marrow) - In addition, used for the treatment of HIV and HTLV
Decitabine Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Chemical Inhibitor; Epigenetic Pathway inhibitor; DNMT Inhibitor Fact: A chemical analogue of cytidine (C). *Deoxy derivative of azacitidine* (also known as 5-aza-2′deoxycytidine). Mechanism of action (MOA): -Similar to azacitidine. -Although decitabine *can only be incorporated into DNA strands* while azacitidine can be incorporated into both DNA and RNA chains.* Administration: I.V. infusion or injection under the skin Toxicity: Same as Azacitidine. Clinical applications: myelodysplastic syndrome (MDS), AML
Vorinostat Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Chemical Inhibitor; Epigenetic Pathway inhibitor; HDAC inhibitors Fact: -Also known as suberanilohydroxamic acid (suberoyl+anilide+ hydroxamic acid abbreviated as *SAHA*). -A member of a larger class of compounds that inhibit HDAC. Mechanism of action (MOA): -Binds to the active site of HDACs. -Acts as a chelator for Zinc ions in the active site of HDACs. -Results in the accumulation of acetylated histones and acetylated proteins. Administration: Oral administration. Toxicity: -*Edema* (abnormal accumulation of fluid in the interstitium, which are locations beneath the skin or in one or more cavities of the body. It is clinically shown as swelling), -fatigue, GI (diarrhea, constipation), -proteinuria (means the presence of an excess of serum proteins in the urine). Clinical applications: The first HDAC inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of *cutaneous T cell lymphoma (CTCL)* on October 6, 2006.
Erlotinib Class: Fact: MOA: Administration: Metabolism: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Chemical Inhibitor; Protein Kinase Inhibitor Fact: A small molecule inhibitor of the tyrosine kinase domain associated with the EGFR. Mechanism of action (MOA): Inhibits *EGFR tyrosine kinase* leading to inhibition of EGFR signaling. Administration: Oral administration. Metabolism: -Metabolized in the liver by the *CYP3A4 enzyme system* -Elimination is mainly hepatic with excretion in feces. Caution must be taken when using these agents with drugs that are also metabolized by the liver CYP3A4 system, such as *phenytoin and warfarin*. Toxicity: Acute toxicity: Diarrhea Delayed toxicity: Skin rash, diarrhea, anorexia, *interstitial lung disease* Clinical applications: Non-small cell lung cancer, pancreatic cancer
Imatinib (Gleevec) Class: Fact: MOA: Administration and Excretion: Toxicity: Clinical Applications: Comments:
Class: Cancer Drug; Targeted Therapy; Chemical Inhibitor; Protein Kinase Inhibitor Fact: An inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein. MOA: -Inhibits *Bcr-Abl tyrosine kinase* and *other receptor tyrosine kinases*, e.g. platelet-derived growth factor receptor (PDGFR), stem cell factor, and c-kit. -Prevents phosphorylation of the kinase substrates by ATP. Administration and excretion: -Well absorbed orally. -Metabolized in the liver, mainly by the CYP3A4 liver microsomal enzyme. -A large fraction of the drug is eliminated in feces via the hepatobiliary route (biliary excretion). Toxicity: Acute toxicity:Nausea and vomiting Delayed toxicity: *Myelosuppression, GI, skin, fluid retention with ankle and periorbital edema*, diarrhea, myalgias, congestive heart failure Clinical applications: CML, gastrointestinal stromal tumor (GIST), *Philadelphia chromosome-positive ALL, AML* Comments on Chronic myelogenous leukemia (CML): -A pluripotent hematopoietic stem cell disorder *characterized by the t(9:22) Philadelphia chromosomal translocation.* _This translocation results in the *Bcr-Abl fusion protein*, the causative agent in CML, and is present in up to 95% of patients with this disease. -*Philadelphia chromosome is found in >95% of CML; 25-30% of adult ALL, 2-10% in pediatric ALL, occasionally in AML*
Crizotinib Class: MOA: Administration: Toxicity: Clinical Applications: Comments:
Class: Cancer Drug; Targeted Therapy; Chemical Inhibitor; Protein Kinase Inhibitor MOA: -Functions as an *ALK* (anaplastic lymphoma kinase) and ROS1 *(c-ros oncogene 1) inhibitor.* -Compete for binding within the ATP-binding pocket of target kinases. -~ 4% of patients with non-small cell lung carcinoma (NSCLC) have a *chromosomal rearrangement that generates a fusion gene between EML4* (echinoderm microtubule-associated protein-like 4) *and ALK*, leading to constitutive ALK kinase activity that contributes to carcinogenesis. -Inhibits the fusion ALK kinase activity and the growth, migration, and invasion of malignant cells Administration: Oral administration. Toxicity: nausea, vomiting, rash or diarrhea, *trail of lights phenomena* (Trails' from lights in peripheral vision in low light conditions) Clinical applications: non-small cell lung carcinoma (NSCLC) Comments: Undergoing clinical trials testing its safety and efficacy in *anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.*
Bortezomib Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Chemical Inhibitor; Proteosome Inhibitor Fact: -Originally named *PS-341*; marketed as *Velcade* by Millennium Pharmaceuticals and *Cytomib* by Venus Remedies) -*The first therapeutic proteasome inhibitor* to be tested in humans. Mechanism of action (MOA): -The *boron atom* in bortezomib binds the catalytic site of the 26S proteasome. -The 26S proteosome plays a role in maintaining the immortal phenotype of myeloma cells, and in solid tumor cancers. Administration: I.V. administration. Toxicity: *Peripheral neuropathy, gastro-intestinal (GI) effects (constipation, nausea)*, myelosuppression, neutropenia, thrombocytopenia, shingles, asthenia. Clinical applications: multiple myeloma, mantle cell lymphoma
Temsirolimus Class: Fact: MOA: Administration: Metabolism: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Chemical Inhibitor; mTOR Inhibitors Fact: A derivative of sirolimus. A mTOR inhibitor and an immunosuppressive agent as well. Mechanism of action (MOA): Same as the MOA of Everolimus. Administration: I.V. administration Metabolism: It is metabolized hepatically via CYP450 3A4. Toxicity: fatigue, skin rash, stomatitis, hematologic abnormalities Clinical applications: Renal cancer, breast cancer
Everolimus Class: MOA: Administration: Metabolism: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Chemical Inhibitor; mTOR Inhibitors Mechanism of action (MOA): -A derivative of sirolimus and works as an *inhibitor of mammalian target of rapamycin (mTOR).* -Binds to its protein receptor FKBP12 (FK506 binding protein 12), which directly interacts with *mTORC1*, inhibiting its downstream signaling. Administration: Oral administration Metabolism: hepatically via CYP450 3A4. Toxicity: Lung or breathing problems, infections, kidney failure, delayed wound healing Clinical applications: Renal cell carcinoma (RCC), ER+/HER2-breast cancer -Immunosuppressant to prevent rejection of organ transplants
Flutamide: Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Hormone Therapy Fact: -A non-steroidal antiandrogen drug. -Largely replaced by newer members of this class, such as *bicalutamide* (an oral non-steroidal antiandrogen used in the treatment of prostate cancer), due to better side effect profiles. Mechanism of action (MOA): -An *antagonist of the androgen receptor (AR).* -Competing with testosterone and its metabolite, dihydrotestosterone (DHT) for binding to ARs in the prostate gland. -Prevents testosterone from stimulating the prostate cancer cells to grow. Administration: Oral administration. Toxicity: Gynecomastia, mild liver injury, gastrointestinal side effects *Comments*: one reason bicalutamide is replacing flutamide is that it appears to exhibit these side effects to a lesser degree. Clinical applications: Prostate cancer; additionally, treat excess androgen levels in women, especially in those with polycystic ovary syndrome.
Abiraterone: Class: Fact: MOA: Administration: Prodrug activation: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Hormone Therapy Fact: -An *androgen production inhibitor* from non-gonadal source. -Formulated as the *prodrug abiraterone acetate.* Mechanism of action (MOA): -Inhibits 17 α-hydroxylase/C17,20 lyase *(CYP17A1)*, an enzyme expressed in testicular, adrenal, and prostatic tumor tissues. -Catalyzes two sequential reactions: Step 1: Pregnenolone-->17-α-hydroxy Pregnenolone using *17 α-hydroxylase activity.* Step 2: Form dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its *C17, 20 lyase activity.* Administration: Oral administration, taking the tablets with food. Prodrug activation: Prodrug Abiraterone acetate is cleaved to release free Abiraterone by *plasma esterases in the bloodstream* Toxicity: Urinary tract infection, Hypokalaemia, Hypertension, Diarrhea, Peripheral oedema (the swelling of tissues, usually in the lower *limbs*, due to the accumulation of fluids). Clinical applications: castration-resistant (formerly hormone-resistant or hormone-refractory) prostate cancer
Leuprolide Acetate: Class: Fact: MOA: Administration: Toxicity: Clinical Applications (Cancer & Non-cancer):
Class: Cancer Drug; Targeted Therapy; Hormone Therapy Fact: A gonadotropin-releasing hormone (GnRH) and Luteinizing hormone-releasing hormone (LH-RH) analog. Mechanism of action (MOA): -Acts as an *agonist at pituitary GnRH receptors.* -Indirectly downregulates the secretion of gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). -Leading to reduction in estradiol and testosterone levels in both sexes. Administration: Available as a slow-release implant or subcutaneous/intramuscular injection. Toxicity: Can cause bone pain, gynecomastia, hematuria, impotence, testicular atrophy Clinical applications: -Hormone-responsive cancers such as prostate cancer or breast cancer -Estrogen-dependent conditions (such as endometriosis or uterine fibroids), to treat precocious puberty, and to control ovarian stimulation in In Vitro Fertilization (IVF). It is considered a possible treatment for paraphilias (abnormal sexual desires). *Non cancer*: chronic adrenal disease, steroid abuse.
Anastrozole Class: Fact: MOA: Administration: Toxicity: Clinical Applications: Comments
Class: Cancer Drug; Targeted Therapy; Hormone Therapy Fact: A non-steroidal aromatase inhibitor. Mechanism of action (MOA): -Binds reversibly to the *aromatase enzyme* through competitive inhibition. -Inhibits the conversion of androgens to estrogens in peripheral tissues (extra-gonadal), thus *inhibits the synthesis of estrogen.* Administration: Oral administration Toxicity: *arthralgias (joint pain)*, bone weakness, dyspnea, peripheral edema, nausea, diarrhea, hot flushes. Clinical applications: Only *postmenopausal women* with localized ER+ breast cancer. *Comments: This class of drugs is more effective than previous drugs such as tamoxifen and crucially, it has fewer side effects".*
Tamoxifen: Class: Fact: MOA: Administration: Toxicity: Prodrug Metabolism: Clinical Applications (Cancer & Non-cancer)
Class: Cancer Drug; Targeted Therapy; Hormone Therapy Fact: The most familiar example of hormonal therapy in oncology: Use of the *selective estrogen-response modulator (SERM)* tamoxifen for the treatment of breast cancer. Mechanism of action (MOA): -Belongs to *SERMs.* -*An antagonist of the estrogen receptor.* -Metabolized into compound (4-hydroxytamoxifen) that also binds to the estrogen receptor but do not activate it. -Preventing estrogen from binding to its receptor. Hence breast cancer cell growth is blocked. Administration: Oral administration Toxicity: *Increase the risk of endometrial cancer*, blood clots, central nerve system (reduced cognition), risk of cataracts Prodrug metabolism: -*A prodrug*, having relatively little affinity for its target protein, the estrogen receptor. -Metabolized in the liver by the *cytochrome P450 isoform CYP2D6 and CYP3A4* into active metabolites [such as 4-hydroxytamoxifen (afimoxifen) and N-desmethyl-4-hydroxytamoxifen (endoxifen)] which have 30-100 times more affinity with the estrogen receptor than tamoxifen itself. Clinical applications: Cancer: nearly all pre-menopausal women with hormone receptor-positive (ER+) breast cancer. Non cancer: McCune-Albright syndrome, infertility, gynecomastia, bipolar disorder
Raloxifene Class: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Hormone Therapy Mechanism of action (MOA): -Similar to tamoxifen. It belongs to SERMs. -Different from tamoxifen, it does not to promote endometrial cancer. Administration: oral administration Toxicity: blood clots, leg swelling/pain, trouble breathing, chest pain, vision changes, developmental abnormalities such as birth defects. *Different from Tamoxifen*, it does not to promote endometrial cancer, does not increase the risk of cataracts. Clinical applications: - Breast cancer in post-menopausal women - Prevention of osteoporosis in post-menopausal women
T-DM1 (Trastuzumab Emtansine) Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Immunotherapy; Antibody Therapy; Conjugated Monoclonal Antibodies Fact: -Full name:Trastuzumab Emtansine -Also known as *antibody-drug conjugates (ADCs)*. (The drug is often too powerful to be used on its own - it would cause too many side effects if not attached to an antibody.) Mechanism of action (MOA): -Targets the HER2 protein, attached to a chemo drug called DM1 (DM1: Derivative of Maytansine, a microtubule destablizing agent). -Same as Trastumuzab, except for carrying a chemo drug DM1. Administration: I.V. administration. Toxicity: Fever, chills, weakness, headache, nausea, vomiting, diarrhea, rashes Clinical applications: Advanced HER2 positive breast cancer
Ipilimumab Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Immunotherapy; Antibody Therapy; Naked Monoclonal Antibodies Fact: -Also known as MDX-010 and MDX-101, marketed as Yervoy. -A human *antibody that binds to CTLA-4* (cytotoxic T lymphocyte-associated antigen 4) Mechanism of action (MOA): -Binds and activates the immune system by targeting CTLA-4 (CTLA-4 is a protein receptor that downregulates the immune system). -Cancer cell antigens (antigens that are produced by cancer cells), can be recognized by dendritic cells, which present the antigens to CTLs (cytotoxic T lymphocytes). -CTLA-4 inhibits the CTLs activation. -*Ipilimumab blocks the CTLA-4 inhibitory signal*, and allows the CTLs to destroy the cancer cells. Administration: I.V. infusion Toxicity: Immune related side effects such as: fever, colitis, rash Clinical applications: Melanoma, small cell and non-small cell lung cancer, prostate cancer
Rituximab Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Immunotherapy; Antibody Therapy; Naked Monoclonal Antibodies Fact: A chimeric *monoclonal antibody against the protein CD20.* Mechanism of action (MOA): -Binds to CD20. (CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation). -Sticks to one side of cancerous B cells, forming a cap and drawing proteins over to that side (asymmetric protein cluster). -The cap enhanced the effectiveness of natural killer (NK) cells in destroying these diseased cells. (When an NK cell latched onto the cap, it had an 80% success rate at killing the B cell). Administration: I.V. infusion. Toxicity: *Severe infusion reaction*, cardiac arrest, cytokine release syndrome, immune toxicity, pulmonary toxicity, bowel obstruction and perforation. Clinical applications: -*Hematological cancers*: leukemias and lymphomas, including Hodgkin's lymphoma. -*Autoimmune diseases*: rheumatoid arthritis. -*Anti-rejection treatment for organ transplants*: Rituximab is now being used off-label (Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, unapproved dosage, or unapproved form of administration) in the management of kidney transplant recipients.
Cetuximab Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Immunotherapy; Antibody Therapy; Naked Monoclonal Antibodies Fact: A chimeric monoclonal antibody *against the extracellular domain of the EGFR.* Mechanism of action (MOA): -Binds to EGFR and inhibits downstream EGFR signaling; enhances response to chemotherapy and radiotherapy. -Its efficacy is restricted to only those patients *whose tumors express wild-type KRAS* (KRAS protein is a GTPase and is an early player in many signal transduction pathways. The mutation of a KRAS gene is an essential step in the development of many cancers). Administration: I.V. infusion. Toxicity: Acute toxicity: Infusion reaction Delayed toxicity: Skin rash, hypomagnesemia, fatigue, interstitial lung disease Clinical applications: Colorectal cancer, head and neck cancer (used in combination with radiotherapy), non-small cell lung cancer
Bevacizumab Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Immunotherapy; Antibody Therapy; Naked Monoclonal Antibodies Fact: A recombinant humanized monoclonal *antibody* that targets all forms of *VEGF-A.* Mechanism of action (MOA): -Binds to and prevents VEGF-A from interacting with VEGF receptors. -Leads to inhibition of VEGF signaling; inhibits tumor vasculature. Administration: I.V. administration Toxicity: Acute toxicity: Hypertension, infusion reaction Delayed toxicity: *Arterial thromboembolic events* (transient ischemic attack, stroke, angina, and myocardial infarction), gastrointestinal perforations, wound healing complications, proteinuria Clinical applications: Colorectal cancer, breast cancer, non-small cell lung cancer, renal cell cancer
Trastuzumab Class: Fact: MOA: Administration: Toxicity: Significant complications (comments): Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Immunotherapy; Antibody Therapy; Naked Monoclonal Antibodies Fact: -A monoclonal *antibody against HER2/neu receptor.* -Newest agent: T-DM1 (Trastuzumab Emtansine) - links HER2 antibody to cytotoxic cross-linking agent - (see slide regarding conjugated mAb) Mechanism of action (MOA): *-Binds to domain IV of the extracellular segment of the HER2 receptor*, blocking EGF (Epidermal growth factor) pathway. [EGF pathway receptors: HER1 (EGFR), *HER2*, HER3, and HER4] -In cancer cells, the HER2 protein can be expressed *up to 100 times more* than in normal cells (2 million versus 20,000 per cell). Administration: I.V. infusion. Toxicity: Unique toxicity: *Infusion-related reactions*, flu-like symptoms (such as fever, chills and mild pain), nausea and diarrhea. Significant complications: Trastuzumab is *associated with cardiac dysfunction* in 2-7% of cases. As a result, regular cardiac screening is commonly undertaken during the trastuzumab treatment period. Comments: Trastuzumab downregulates neuregulin-1 (NRG-1), which is essential for the activation of cell survival pathways in cardiomyocytes and the maintenance of cardiac function. These are all significant for the function and structure of cardiomyocytes. *Trastuzumab can therefore lead to cardiac dysfunction.* Clinical applications: HER2-positive breast cancer
Interferon alpha Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Immunotherapy; Cytokine Therapy Fact: -Interferons (IFNs) are cytokines produced by the immune system. -Involved in anti-viral response, but also have use in the treatment of cancer. -Three groups of IFNs: *type I (IFNα and IFNβ)*, type II (IFNγ) and the relatively newly discovered type III (IFNλ). -Although both type I and II IFNs promote the anti-tumor effects of the immune system, *only type I IFNs have been shown to be clinically effective in cancer treatment.* -IFNλ has been tested for its anti-tumor effects in animal models, and shows promise. Mechanism of action (MOA): Promotes the anti-tumor effects of the immune system by increasing major histocompatibility complex (MHC) expression and increasing immune effector T and natural killer cells. Administration: Intramuscular injection or injection under skin. Toxicity: malaise, fatigue, fever, "flu-like symptoms" (increased body temperature, feeling ill, fatigue, headache, muscle pain, convulsion, dizziness, hair thinning, and depression), immunosuppression Clinical applications: hairy-cell leukemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukemia and melanoma
Interleukin 2 Class: Fact: MOA: Administration: Toxicity: Clinical Applications:
Class: Cancer Drug; Targeted Therapy; Immunotherapy; Cytokine Therapy Fact: -Interleukin-2 (IL-2) is a member of a group of specific immune system signaling cytokines called interleukins (ILs). -ILs send chemical messages between leukocytes (also known as white blood cells). Mechanism of action(MOA): -IL-2 functions *in the proliferation of cytotoxic T-cells* as an immune response to an antigen reaching a T-cell receptor on a leukocyte. -These cytotoxic T-cells have the function of destroying infected, diseased, or tumor-characterized cells. *-IL-2 enhances T-cell response against cancerous cells.* Administration: I.V. or inject under skin Toxicity: May lead to capillary leak syndrome, fevers, renal and liver failure Clinical applications: renal cell carcinoma, melanoma
Irinotecan Class: Fact: MOA: Administration: Prodrug metabolism: Excretion: Toxicity Comments: Clinical applications
Class: Cancer Drug; Topoisomerase I inhibitors; Camptothecins Fact: A camptothecin (natural products derived from the Camptotheca acuminata tree originally found in China.) analog used in clinical practice in the USA. MOA: -Inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating *single DNA strands (SS).* -Inhibition of TopoI results in DNA damage. Administration: I.V. administration Prodrug metabolism: -A prodrug that is converted mainly in the liver by the *carboxylesterase enzyme to the SN-38 metabolite.* -SN-38 metabolite is 1000-fold more potent as *an inhibitor of topoisomerase I* than the parent compound. Excretion: Mainly eliminated in *bile and feces*, and dose reduction is required in the setting of liver dysfunction. Toxicity: Acute toxicity: Diarrhea, nausea, vomiting, cholinergic reaction (facial flushing, abdominal cramping) Delayed toxicity: *Myelosuppression and diarrhea* are the two most common adverse events. Comments: There are two forms of diarrhea: -*Early form* that occurs within 24 hours after treatment, and is thought to be a cholinergic event effectively treated with atropine. -*Late form* that usually occurs 2-10 days after treatment, which can be severe, *leading to significant electrolyte imbalance and dehydration in some cases.* Clinical applications: Colorectal cancer (first-line therapy when used in combination with *5-FU* and leucovorin), gastroesophageal cancer, non-small cell and small cell lung cancer
Etoposide (VP-16) Class: Fact: MOA: Administration: Excretion: Toxicity: Clinical Applications:
Class: Cancer Drug; Topoisomerase II Inhibitors; Epipodophyllotoxins Fact: A semisynthetic derivative of podophyllotoxin, which is extracted from the mayapple root (Podophyllum peltatum). MOA: Inhibits the DNA enzyme *topoisomerase II*, the key enzyme responsible for cutting and religating *double DNA strands* (DS). Inhibition of this enzyme results in DNA damage. Administration: -I.V. and oral formulations of etoposide are approved for clinical use in the USA. -Oral bioavailability is about 50%, requiring the oral dose to be twice that of an I.V. dose. Excretion: Up to 30-50% of drug is excreted in the urine, and dose reduction is required in the setting of renal dysfunction. Toxicity: -Acute toxicity:Nausea, vomiting, hypotension -Delayed toxicity: *Myelosuppression*, alopecia -Unique complication of this class: *Secondary malignancies* Clinical applications: Non-small cell and small cell lung cancer; non-Hodgkin's lymphoma, gastric cancer, germ cell cancer *In addition*, it is effective in high-dose regimens in the transplant setting for breast cancer and lymphomas.
Leucovorin
Class: Cancer Drug; folate analog Mechanism of Action: Leucovorin Rescue -reduced form of folic acid (5-CHO-THF). - *bypasses DHFR step in folic acid synthesis.* - Administration of leucovorin or by L-leucovorin can *reverse the biologic effects of MTX.* - Leucovorin rescue is used in conjunction with high-dose (>1,000 mg/m2) MTX therapy to rescue normal cells from undue toxicity, and it has also been used in cases of accidental drug overdose.
Mesna
Cyclophosphamide Rescue Therapy -Used as an *adjuvant* in cancer chemotherapy involving *cyclophosphamide.* -Its name is an acronym for 2-mercaptoethane sulfonate Na (Na being the chemical symbol for sodium). -Used therapeutically to *reduce the incidence of hemorrhagic cystitis and hematuria* when a patient receives cyclophosphamide for cancer chemotherapy. Cyclophosphamide *may be converted to urotoxic metabolites, such as acrolein* in vivo. Mesna assists to detoxify these metabolites and it also increases urinary excretion of cysteine.
Anthracyclines Fact: Common MOA:
Fact: -Isolated from Streptomyces peucetius var caesius. -Among the most widely used cytotoxic anticancer drugs. Common mechanisms of action (MOA): -Inhibition of topoisomerase II. -Binding to DNA through *intercalation*, leading to *blockade of DNA and RNA synthesis*, and *DNA strand scission*. -Generation of semiquinone *free radicals* and oxygen free radicals through an iron-dependent, enzyme-mediated reductive process. -Binding to cellular membranes to alter fluidity and ion transport.
