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Anticancer Drugs • Cancer – Uncontrolled multiplication and spread within the body of abnormal forms of body's own cells Cancer chemotherapy not as successful as antimicrobial chemotherapy • Metabolism in parasite differs qualitatively from host cells, while metabolism in cancer cells differ only quantitatively from normal host cells – Hence target selectivity is more difficult in cancer – cancer there is no substantial immune response – Diagnostic complexity: delay in institution of treatment Cancer cells differ from normal cells by • Uncontrolled proliferation • De-differentiation & loss of function • Invasiveness • Metastasis General toxicity of cytotoxic drugs • Nausea & Vomiting • Bone marrow depression • Alopecia • Gonads: Oligospermia, impotence, ↓ ovulation • Foetus: Abortion, foetal death, teratogenicity • Carcinogenicity • Hyperuricemia • Immunosupression: Fludarabine • Hazards to staff Modalities of treatment in cancer • Surgery • Radiotherapy • Chemotherapy: 50 % of the patients can be treated with chemotherapy contributing to cure in 15 -20 % of patients (in surgery & radiotherapy 1/3 of patients can be cured, effective when tumor has not metastasized) Phases of cell cycle CLASSIFICATION - II: Depending on mechanism at cell level • Directly acting cytotoxic drugs: – Alkylating agents – Antimetabolites – Natural products • Antibiotics • Vinca alkaloids • Taxanes • Epipodophyllotoxins • Camptothecin analogs • Enzymes • Biological response modifiers – Miscellaneous: Cisplatin, carboplatin • Indirectly acting- by altering the hormonal mileau : – Corticosteroids – Estrogens & ERMs – 5 alpha reductase inhibitors – Gnrh agonists – Progestins Alkylating agents • Nitrogen Mustards – Meclorethamine, Melphalan, Chlorambucil, cyclophosphamide, ifosfamide • Ethyleneimine : Thiotepa • Alkyl Sulfonate: Busulfan • Nitrosureas – Carmustine,lomustine, streptozocin • Triazines – Dacarbazine, temozolamide Antimetabolites • Folate Antagonists – Methotrexate • Purine Antagonists – 6 Mercaptopurine, 6 Thioguanine, Azathioprine • Pyrimidine antagonists – 5 Fluorouracil, cytarabine, gemcitabine Natural Products • Antibiotics – Actinomycin D, Doxorubicin, Daunorubicin, Bleomycin, Mitomycin C • Vinca alkaloids – Vincristine, Vinblastine, Vinorelbine • Taxanes – Paclitaxel, docetaxel • Enzymes – L-Asparginase • Epipodophyllotoxins – etoposide, tenoposide • Camptothecin analogs – Topotecan, irinotecan • Biological response modifiers – Interferons, – Interleukins Miscellaneous Agents • Cisplatin • Carboplatin • Hydroxurea • Procarbazine • Mitotane • Imatinib Hormones & antagonists • Corticosteroids – Prednisolone • Estrogens – Ethinyl Estradiol • SERM – Tamoxifene, Toremifene • SERD – Fulvestrant • Aromatase Inhibitors – Letrozole, Anastrazole, Exemestane • Progestins – Hydroxyprogesterone • Anti-androgens – Flutamide, Bicalutamide • 5- reductase Inhibitors – finasteride, dutasteride • GnRH analogs – Naferelin, goserelin, leuoprolide ALKYLATING AGENTS • Chemically reactive compounds that combine most readily with nucleophilic centers. • The term ‘alkylating agents’ is applied to compounds which, in a sense, alkylate the substance with which they react, by joining it through a covalent bond. MECHANISM OF ACTION • Contain chemical groups that can form covalent bonds with particular nucleophilic substances in the cell. • Produce highly reactive carbonium ion intermediates. • Forms covalent bond with electron donors like amine, hydroxyl and sulfhydryl groups. • Alkylating agents are bifunctional, i.e. they have two alkylating groups. • The nitrogen at position 7 (N7) of guanine, being strongly nucleophilic, is probably the main molecular target for alkylation in DNA. • N1 and N3 of adenine and N3 of cytosine may also be affected. • Being bifunctional they can cause intra- or interchain cross-linking, abnormal base pairing or chain scission which causes cell death,gene mutation or carcinogenesis. • Destroy DNA structure directly, has strong toxicity to both proliferate or nonproliferate cells—Cell cycle non-specific agents • Results in a block at G2 and subsequent apoptotic cell death. NITROGEN MUSTARDS MECHANISM OF ACTION • Nitrogen mustards inhibit cell reproduction by binding irreversibly with the nucleic acids (DNA). • The specific type of chemical bonding involved is alkylation. • After alkylation, DNA is unable to replicate and therefore can no longer synthesize proteins and other essential cell metabolites. • Consequently, cell reproduction is inhibited and the cell eventually dies from the inability to maintain its metabolic functions. MECHLORETHAMINE MECHANISM OF ACTION:• Transported into the cell by a choline uptake process. • Loses a chloride ion and forms a reactive intermediate • That alkylates the N7 nitrogen of a guanine residue in one or both strands of a DNA molecule. • Alkylation leads to cross-linkages that facilitates DNA strand breakage. • Occur in both cycling and resting cells (therefore cell-cycle nonspecific) • Proliferating cells are more sensitive to the drug, especially those in G1 and S phases. PHARMACOKINETICS • Very unstable, and solutions must be made up just prior to administration. • Mechlorethamine is also a powerful vesicant (blistering agent) • Administered only IV, because it can cause severe tissue damage if extravasations occurs. • • • • RESISTANCE Decreased permeability of the drug Increased conjugation with thiols such as glutathione Possibly increased DNA repair. ADVERSE EFFECTS • Severe nausea and a vomiting. • Bone marrow depression • Immunosuppression. • Extravasation - a serious problem. THERAPEUTIC APPLICATIONS • Primarily in the treatment of Hodgkin's disease as part of the MOPP regimen (Mechlorethamine, Oncovin, Prednisone, Procarbazine) • Also useful in the treatment of some solid tumors. CYCLOPHOSPHAMIDE AND IFOSFAMIDE • Very closely related mustard agents that share most of the same toxicities. • They are unique in that (1) They can be taken orally, and (2) They are cytotoxic only after generation of their alkylating species, following their hydroxylation by cytochrome P-450. MECHANISM OF ACTION • Most commonly used • Both cyclophosphamide and ifosfamide are first biotransformed to hydroxylated intermediates by the cytochrome P-450 system. • The hydroxylated intermediates undergo breakdown to form the active compounds, phosphoramide mustard and acrolein. • Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step. RESISTANCE • Increased DNA repair • Decreased drug permeability • Reaction of the drug with thiols(for example, glutathione). • Cross-resistance, however, does not always occur. PHARMACOKINETICS • Preferentially administered by the oral route. • Minimal amounts of the parent drug are excreted into the feces (after biliary transport), or into the urine by glomerular filtration. ADVERSE EFFECTS • Alopecia, • Nausea, • Vomiting, • Diarrhoea • Bone marrow depression, • Leukocytosis • Hemorrhagic cystitis • Other toxicities on the germ cells resulting in amenorrhea, testicular atrophy, and sterility. • High incidence of neurotoxicity in patients on high-dose ifosfamide. USES OF CYCLOPHOSPHAMIDE • Neoplastic conditions – Hodgkins and non hodgkins lymphoma – Multiple myeloma – Burkits lymphoma – Neuroblastoma , retinoblastoma – Breast Cancer, adenocarcinoma of ovaries • Non neoplastic conditions – Rheumatoid arthritis – Nephrotic syndrome IFOSFAMIDE • Congener of cyclophosphamide • Longer half life than cyclophosphamide • Less alopecia and less emetogenic than cyclophosphamide • Can cause hemorrhagic cystitis and severe neurological toxicity • Used for germ cell testicular tumors and adult sarcomas • Bronchogenic, breast, testicular, bladder, head and neck carcinomas, osteogenic sarcoma and some lymphomas. MELPHALAN • Very effective in MULTIPLE MYELOMA & advanced ovarian cancer • Less irritant locally , less alopecia • Adverse Effects : – Bone marrow Depression – Infections , diarrhea and pancreatitis THIO-TEPA • Triethylenephosphoramide • • • • Does not require to form active intermediate Active intravesicular agent can also be used topically in superficial bladder cancer Not well absorbed orally given IV High toxicity BUSULFAN • Highly specific for myeloid elements • Little effect on lymphoid tissue and G.I.T. ADVERSE EFFECT:• Hyperuricaemia; Pulmonary fibrosis & Sterility • Drug of choice for chronic myeloid leukemia. NITROSOUREA • Carmustine and lomustine are closely related nitrosoureas. MECHANISM OF ACTION • The nitrosoureas exert cytotoxic effects by an alkylation that cross-links strands of DNA to inhibit its replication and eventually RNA and protein synthesis. • Although they alkylate DNA in resting cells, cytotoxicity is expressed only on cell division; therefore nondividing cells can escape death if DNA repair occurs. RESISTANCE • True nature of resistance is unknown • Probably results from DNA repair and reaction of the drugs with thiols. PHARMACOKINETICS • In spite of the similarities in their structures, carmustine - intravenously, lomustine - orally. • Distribute to many tissues, • Ability to readily penetrate into the CNS. • The drugs undergo extensive metabolism. • Lomustine is metabolized to active products. • The kidney is the major excretory route. ADVERSE EFFECTS • Delayed hematopoietic depression • An aplastic marrow • Renal toxicity • Pulmonary fibrosis THERAPEUTIC APPLICATIONS • Primarily employed in the treatment of brain tumors. • They find limited use in the treatment of other cancers. Triazenes • Dacarbazine – Primary inhibitory action on RNA & protein synthesis – Used in malignant melanoma, Hodgkin's disease • Temozolamide – New alkylating agent – Approved for malignant glioma – Rapidly absorbed after oral absorption & crosses BBB ANTIMETABOLITES • • • • These are analogues related to normal components of DNA or of coenzymes involved in nucleic acid synthesis. They competitively inhibit utilization of the normal substrate or get themselves incorporated forming dysfunctional macromolecules. They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. Their maximal cytotoxic effects are S phase (and-therefore cell-cycle)specific. METHOTREXATE • Structurally related to folic acid • Acts as an antagonist of that vitamin by inhibiting dihydrofolatereductase ,the enzyme that convert folic acid to its active form coenzyme form tetrahydrofolic acid (THF4). • It therefore acts as an antagonist of that vitamin. • Folate plays a central role in a variety of metabolic reactions involving the transfer of one-carbon units. MECHANISM OF ACTION (a) Inhibition Of DihydrofolateReductase: • After absorption of folic acid from dietary sources or from that produced by intestinal flora, the vitamin undergoes reduction to the tetrahydrofolate form (FH4) by the intracellular NADPH-dependent dihydrofolate reductase. • Methotrexate enters the cell by an active transport process, which normally mediates the entry of N5-methyl FH4. • At high MTX concentrations, the drug can diffuse into the cells. • MTX has an unusually strong affinity for dihydrofolate reductase, and effectively inhibits the enzyme. • Its inhibition can only be reversed by a thousand-fold excess of the natural substrate, dihydrofolate or by administration of leucovorin, which bypasses the blocked enzyme and replenishes the folate pool. (b) Consequences Of Decreased FH4: • Inhibition of dihydrofolatereductase deprives the cell of the various folate coenzymes and leads to decreased biosynthesis of thymidylic acid, methionine and serine, and the purines (adenine and guanine). • Thus eventually to depressed DNA, RNA and protein synthesis and to cell death. c. Polyglutamated MTX: • Like tetrahydrofolate itself, MTX becomes polyglutamated within the cell, a process that favors intracellular retention of the compound due to its larger size and increased negative charge • RESISTANCE • Nonproliferating cells are resistant to methotrexate. • Due to amplification (production of additional copies) of the gene that codes for dihydrofolate reductase resulting in increased levels of this enzyme. • Enzyme affinity also be diminished. • Reduced influx of MTX, caused by a change in the carrier-mediated transport responsible for pumping MTX into the cell. THERAPEUTIC APPLICATIONS • Methotrexate, often in combination with other drugs, is effective against acute lymphocytic leukemia, choriocarcinoma, Burkitt's lymphoma in children, breast cancer, and head and neck carcinomas. • High-dose MTX is curative for osteogerric sarcoma and choriocarcinoma; treatment is followed by administration of leucovorin to rescue the bone marrow. • In addition, low-dose MTX is effective as a single agent against certain inflammatory diseases, such as severe psoriasis and rheumatoid arthritis. Pharmacokinetics • • • • a. Administration and distribution: Methotrexate is readily absorbed at low doses from the GI tract, but it can also be administered by intramuscular (IM), intravenous (IV), and intrathecal routes. High concentrations of the drug are found in the intestinal epithelium, liver and kidney, as well as in ascites and pleural effusions. MTX is also distributed to the skin. b. Fate: • Although folates found in the blood have a single terminal glutamate, most intracellular folates are converted to polyglutamates. • Methotrexate is also metabolized to poly-glutamate derivatives. • High doses of methotrexate undergo hydroxylatlon at the 7 position. • This derivative is less water soluble, and may lead to crystalluria. • Therefore, it is important to keep the-urine alkaline and the patient well hydrated to avoid renal toxicity. • Excretion of the parent drug and the 7-OH metabolite occurs via the urine. 5. Adverse effects: a. Commonly observed toxicities: • Most frequent toxicities are stomatitis, myelosuppression, erythema, rash, urticaria, alopecia, nausea, vomiting, and diarrhea. b. Renal damage: • Although uncommon during conventional therapy, renal damage is a complication of high-dose methotrexate. c. Hepatic function: • Hepatic function should be monitored. • Long term use may lead to fibrosis. d. Pulmonary toxicity: • Children being maintained on methotrexate may develop cough, dyspnea, fever, and cyanosis. e. Neurologic toxicities: • These are associated with intrathecaladministralion, and include subacute meningeal irritation, stiff neck, headache, and fever. • Seizures, encephalopathy, or paraplegia occur rarely. • Long-lasting effects, such as learning disabilities. f. Contraindications: • Because methotrexate is teratogerlic and an abortifacient it should be avoided in pregnancy. Purine antagonists 6-MERCAPTOPURINE • The drug ,6 mercaptopurine (6-MP) is the thiolanalog of hypoxanthine. • It and thioguanine (6-TG) were the first purine analogs to prove benificial for treating neoplastic disease. • Azathioprine, an immunosuppressant, exerts its effects after conversion to 6-MP. SITE OF ACTION: • a. Formation of nucleotide: • To exert its antileukemic effect, 6- mercaptopurine must penetrate target cells and be converted to the corresponding nlucleotide, 6-mercaptopurine ribose phosphate. • The addition of the ribose phosphate is catalyzed by the salvage pathway enzyme, hypoxanthine- guanine phosphoribosryl -transferase (HGPRT). b. Inhibition of purine synthesis: • Inhibit the first step of de novo purine ring biosynthesis as well as formation of AMP and xanthinylic acid (XMP) from inosinic acid (IMP). c. Incorporation into nucleic acids: • Dysfunctional RNA and DNA result from incorporation of guanylateanalogs generated from the unnatural nucleotides. • Thio-IMP is dehydrogenated to thio- GMP, which after phosphorylation to di- and triphosphates, can be incorprated into RNA. • The deoxyribonucleotideanalogs that are also formed are incorporated into DNA. MOA 1) 2) 3) 4) 6-mercaptopurine Converted in the cells to ribonucleotide of 6-mercaptopurine Suppresses denovo biosynthesis of purines No DNA synthesis 2. Resistance • Resistance is associated with (1) an inability to biotransform6-MP to the corresponding nucleotide because of dcreased level of HGPRT (2) an increased dephosphorylation; or (3) increased metabolism of the drug to thiouric acid. 3. Therapeutic applications • 6-MP is used principally in the mainteinance of remission in acute lymphoblastic leukemia (ALL). 4. Adverse effects: • Side effects include nausea, vomiting, and diarrhea. • Bone marrow depression is the chief toxicity. • Hepatotoxicity has also been reported. 5. PHARMACOKINETICS a. administration and metabolism: • Absorption by the oral route is erratic. • The drug is widely distributed throughout the body except for the cerebrospinal fluid. • 6-MP undergoes metabolism in the liver to the 6-methyl mercaptopurine (S-CH3) derivative or to thiouric acid. • The latter reaction is catalyzed by xanthine oxidase. • Because allopurinol, a xanthine oxidase inhibitor, is frequently administered to cancer patients receiving chemotherapy to reduce hyperuricemia, • it is important to decrease the dose of 6-MP in these individuals to avoid accumulation of the drug and exacerbation of toxicities. b. Excretion: The parent drug and its metabolites are excreated by the kidney. Fludarabine • Phosphorylates intracellularly to form triphosphate • Inhibits DNA polymerase and gets incorporated to form dysfunctional DNA • Effective in slow growing tumors: (apoptosis) • Use: – Chronic lymphoblastic leukemia (CLL) and non hodgkins • Adverse events: – chills, fever, opportunistic infection, myelosupression Pyrimidine antagonists 5-FLUOROURACIL (5-FU) • A pyrimidine analog, • Fluorouracil is an analogue of thymine in which the methyl group is replaced by a fluorine atom. • A stable fluorine atom at position 5 of the uracil ring. • The fluorine interferes with the conversion of deoxyuridylic acid to thymidylic acid. • Depriving the cell of one of the essential precursors for DNA synthesis. 1. Site of action: - It has two active metabolites: 5-FdUMP and 5-FdUTP. - 5-FdUMP inhibits thymidylatesynthetases and prevents the synthesis of thymidine, a major building block of DNA. - 5-FdUTP is incorporated into RNA by RNA polymerase and interferes with RNA function. MOA 1) 2) 3) 4) 5) 5-fluorouracil Converted to 5-fluoro-2-deoxy uridine monophosphate Inhibits thymidilate synthesis Blocks conversion of deoxyuridilic acid to deoxythymidilic acid Inhibition of DNA synthesis 2.Resistance: • • • Lost the ability to convert 5-FU into active form Altered or increased thymidylatesynthetase Increased rate of 5- FU catabolism. 3. Theraputic applications:• • primarily in the treatment of slowly growing, solid-tumors=(for example: colorectal, breast, ovarian, pancreatic, and gastric carcinomas) Treatment of superficial basal cell carcinomas. 4. Pharmacokinetics: • Severe toxicity to the GI tract • Given intravenously or topically. • Penetrates well into all tissues including the CNS. • Metabolized in the liver 5. Toxicities: • Nausea, vomiting, diarrhea, and alopecia, severe ulceration of the oral and GI mucosa, bone marrow depression and anorexia Cytarabine • Cytosine arabinoside, ara-C • An analog of 2'-deoxycytidine in which the natural ribose residue is replaced by D-arabinose. • Acts as a pyrimidine antagonist. 1. Site of action: • ara-C sequentially phosphorylated to the corresponding nucleotide, • cytosinearabinoside triphosphate (ara-CTP), in order to be cytotoxic. • It is S-phase (hence cell-cycle) specific. • Ara-C is also incorporated into DNA and can terminate chain elongation. 2. Resistance: • Defect in the transport process • A change in phosphorylating enzymes • An increased pool of the natural dCTP nucleotide. 3. Therapeutic indications: • The major clinical use is in acute nonlymphocyticleukemia in combination with 6-TG and daunorubicin. 4. Pharmacokinetics: • Given IV • Distributes throughout the body, but does not penetrate the CNS. • Injected intrathecally • Undergoes extensive oxidative deamination • Excreted by the kidney. 5. Adverse effects: • Nausea, • Vomiting, • Diarrhea • Severe myelosuppression • Hepatic dysfunction • Seizures or altered mental states. GEMCITABINE • S-phase specific • A deoxycytidine antimetabolite • Undergoes intracellular conversion to gemcitabine monophosphate via the enzyme deoxycytidine kinase • it is subsequently phosphorylated to gemcitabine diphosphate and gemcitabine triphosphate • Gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA strands • Due to an addition of a base pair before DNA polymerase is stopped, Gemcitabine inhibits both DNA replication and repair • Gemcitabine-induced cell death has characteristics of apoptosis USES • variety of solid tumors • very effective in the treatment of pancreatic cancer • Small cell lung cancer • carcinoma of the bladder, breast, kidney, ovary, and head and neck Plant Alkaloids Vinca alkaloids • Obtained from periwinkle plant ( VincaRosea) • Vincristine, vinblastine, vinorelbine MECHANISM OF ACTION • Binds to the microtubular protein tubulin in a dimeric form • The drug-tubulin complex adds to the forming end of the microtubules to terminate assembly • Depolymerization of the microtubules occurs • Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation • CCS agents- M phase MOA 1) Vinblastine and Vincristine 2) Bind to β-tubulin (drug tubulin complex) 3) inhibits its polymerization into microtubules 4) No intact mitotic spindle 5) cell division arrested in metaphase Resistance • Enhanced efflux of vincristine and vinblastine and several other drugs. • Alterations in tubulin structure Therapeutic applications Vincristine - Acute leukemias, lymphomas, Wilm’s Tumor and Neuroblastoma Vinblastine – Lymphomas, Neuroblastomas,Testicular cancer and Kaposi’s sarcoma Vinorelbine – non-small cell lung carcinoma and breast Cancer PHARMACOKINETICS • Given Intravenously • Concentrated and metabolized in the liver • Excreted into bile and feces. • Doses must be modified in patients with , impaired hepatic function or biliary obstruction. ADVERSE EFFECTS • a. Shared toxicities: Vincristine and vinblastine • Phlebitis or cellulitis, nausea, vomiting, diarrhea, and alopecia. • b. Unique toxicities: • Vinblastine is a more potent myelosuppressant. • Vincristine associated with peripheral neuropathy, Gastrointestinal problems. TAXANES • Paclitaxel &docetaxel • Plant product obtained from bark of Pacific Yew ( TaxusBrevifolia) & European Yew (TaxusBuccata) PACLITAXEL • Better known as taxol, • Paclitaxel is the first member of ,the taxane family used in cancer chemotherapy. • A semi-synthetic paclitaxel is now available. SITE OF ACTION • Paclitaxel binds reversibly to tubulin • But it promotes polymerization and stabilization of the polymer rather than disassembly. • The overly stable microtubules formed in the presence of paclitaxel are dysfunctional, thereby causing the death of the cell. Resistance • Efflux of the drug • The mutation in tubulin structure. Therapeutic indications • Advanced ovarian cancer and • Metastatic breast cancer. • Small-cell lung cancer, • Squamous-cell carcinoma of the head and neck, • Several other cancers. • Combination therapy with other anticancer drugs PHARMACOKINETICS • Infused over 3-4 hours. • Hepatic metabolism and biliary excretion are responsible for elimination of paclitaxel. ADVERSE EFFECTS • Hypersensitivity • Neutropenia • Peripheral neuropathy • Transient asymptomatic bradycardia • Alopecia • vomiting • Diarrhea Epipodophyllotoxins • Etoposide&tenoposide • Semisynthetic derivatives of podophyllotoxinspodophyllumpeltatum (plant glycoside) MOA 1) 2) 3) 4) Etoposide and Teniposide forms complex with DNA and topoisomerase ІІ prevent resealing of broken DNA strand Cell death • Act in S & G2 phase Etoposide&Teniposide • Teniposide is an analogue with similar properties • PK- orally well absorbed and distributes to most body tissues. Elimination is mainly via kidneys • Clinical use – Testicular and lung ca. in combination with cytotoxic agents. Nonhodgkin’s lymphoma and AIDS related Kaposi’s Sarcoma • Toxicity – Etoposide and Teniposide are GI irritants and cause alopecia and bone marrow suppression CAMPTOTHECINS TOPOTECAN and IRINOTECAN:• Derived from camptothecaaccuminata • Inhibit Topoisomerase I: No resealing of DNA after strand has untwisted PK• Irinotecan – prodrug – converted to active metabolite in liver • Topotecan is eliminated renally • Irinotecan and its metabolite eliminated in bile and faeces • Topotecan: – Used in metastatic ovarian cancer – Major toxicity is bone marrow depression • Irinotecan – Used in metastatic cancer of colon/rectum – Toxicity: diarrhoea, neutropenia, thrombocytopenia, cholinergic side effects ANTIBIOTICS Dactinomycin Mechanism of Action • Intercalates into the minor grooves of double helix between G-C base pairs of DNA ad interferes with the movement of RNA polymerase along the gene preventing transcription. • May also cause strand breaks and stabilise DNA topoisomerase II complex. • Uses: – Wilms tumor, – • gestational choriocarcinoma Adverse effects – bone marrow supression – Irritant like meclorethamine – sensitizes to radiation, and inflammation at sites of prior radiation therapy may occur – Gastrointestinal adverse effects Anthracyclines Mechanism of Action • High-affinity binding to DNA through intercalation, resulting in blockade of DNA and RNA synthesis • DNA strand scission via effects on Top II • Binding to membranes altering fluidity • Generation of the semiquinone free radical and oxygen radicals Toxicity • Bone marrow depression • Total alopecia • Cardiac toxicity Therapeutic Uses • Doxorubicin- carcinomas of the breast, endometrium, ovary, testicle, thyroid, and lung, Ewing’s sarcoma, and osteosarcoma • Daunorubicin- acute leukemia Bleomycins • Group of metal-chelating glycopeptide antibiotics obtained from Streptomyces verticullus. • Produces chelation of copper or iron ions which produces superoxide ions that interacts with DNA. • Degrade preformed DNA, causing chain fragmentation and release of free bases. • Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis • The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations • Cell cycle specific • Active in G2 phase • Uses : • • • Epidermoid cancers of skin, oral cavity, genitourinary tract, esophagus • Testicular tumors • Hodgkins lymphoma Adverse effects: • Pneumonitis • Fatal pulmonary fibrosis • Hyper pigmentation • spares bone marrow Mitomycin CCNS , given intravenously and is rapidly cleared by hepatic metabolism Mechanism of Action • Bioreductive alkylating agent that undergoes metabolic reductive activation through an enzyme-mediated reduction to generate an alkylating agent that crosslinks DNA Toxicity • Severe myelosuppression • Renal toxicity • Interstitial pneumonitis Therapeutic Uses • Squamous cell carcinoma of the cervix • Adenocarcinomas of the stomach, pancreas, and lung • 2nd line in metastatic colon cancer Plicamycin Mechanism of Action • Binds to DNA through an antibiotic-Mg2+ complex • This interaction interrupts DNA-directed RNA synthesis Toxicity • Bleeding disorders • Liver toxicity Therapeutic Uses • Testicular cancer • Hypercalcemia Mitoxantrone • Analogue of doxorubicin with lower cardiotoxicity • It has a narrow range of utility: in acute nonhaemolytic leukaemia, chronic myelogenous leukaemia, non-hodgkin lymphoma and carcinoma breast. • Major toxicity is marrow depression and mucosal inflammation. MISCELLANEOUS CISPLATIN • A member of the platinum coordination complex class • Because of cisplatin's severe toxicity, carboplatin was developed. • The therapeutic effectiveness of the two drugs is similar but their pharmacokinetics, patterns of distribution and dose-limiting toxicities differ. MOA • Similar to that of the alkylating agents. • Cisplatin enters the cell and binds to the N7 of guanine of DNA, forming interand intra-strand crosslinks. • The resulting cytotoxic lesion inhibits both DNA and RNA synthesis. • Both drugs can also bind to proteins and other compounds containing SH groups. • Cytotoxicity can occur at any stage of the cell cycle, but the cell is most vulnerable to the actions of these drugs in GI and S. MOA 1) 2) 3) 4) 5) 6) Cisplatin enters cells (Cl-goes out) Forms highly reactive platinum complexes Intra strand &interstrand cross links DNA damage Inhibits cell proliferation 2.Resistance • Elevated glutathione levels • Increased DNA repair 3. Therapeutic applications • Treatment of solid tumors such as metastatic testicular carcinoma in combination with vinblastine and bleomycin • Ovarian carcinoma in combination with cyclophosphamide • Alone for bladder carcinoma 4. Pharmacokinetics • Cisplatin and carboplatin are administered IV • Given intraperitoneally for ovarian cancer. • Over 90% is bound to serum proteins. • Highest concentrations are found in liver, kidney, intestinal, testicular and ovarian cells, but little penetrates into the CSF. • The renal route is for excretion. 5. Adverse effects • Severe vomiting • Nephrotoxicity • Hypomagnesemia • Hypocalcemia • Ototoxicity and tinnitus • Mild bone marrow suppression • Neurotoxicity • Hypersensitivity reactions. • Myelosuppression. CARBOPLATIN • Better tolerated • Nephrotoxicity , ototoxicity , neurotoxicity low • Less emetogenic • But thrombocytopenia and leukopenia may occur • Less plasma protein binding • Use: – primarily in ovarian cancer of epithelial origin – Squamous cell carcinoma of head and neck L-Asparaginase • Catalyzes the deamination of asparagine to aspartic acid and ammonia. • Enzyme used chemotherapeutically • Derived from bacteria. 1. Mechanism of action - Some neoplastic cells require an externalsource of asparagine - Because of their limited capacity to make sufficient L-asparagine to support growth and function. - L-Asparaginasehydrolyzes blood asparagine and thus deprives the tumor cells of this nutrient required for protein synthesis. 2. Resistance: • Increased capacity of tumor cells to synthesize asparagine 3. Therapeutic application: • Childhoodacute lymphocytic leukemia in combination with vincristine and prednisone. 4. Pharrnacokinetics: • Administered either IV or IM • Because it is destroyed by gastric enzymes. 5. Adverse effects: • Hypersensitivity reactions • Decrease in clotting factors • Liver abnormalities, • Pancreatitis, • Seizures and coma Procarbazine MOA: • forms hydrogen peroxide, which generates free radicals that cause DNA damage • Inhibits DNA and RNA synthesis. • Used in the treatment of Hodgkin's disease as part of the "MOPP regimen and also other cancers. • Procarbazine rapidly equilibrates between the plasma and the CSF after oral or parenteral administration. • Drug are excreted through the kidney. Toxicity • Bone marrow depression • Nausea • vomiting • Diarrhea • Neurotoxic, causing symptoms drowsiness to hallucinations to paresthesias. • A disulfiram-type reaction • Procarbazine is both mutagenic and teratogenic. HYDROXYUREA MOA:• It blocks the conversion of ribonucleotides to deoxyribonucleotides by inhibiting the enzyme ribonucleoside diphosphate reductase-thus interferes with DNA synthesis. • Exerts S-phase specific action. Therapeutic value:• chronic myeloid leukaemia, psoriasis and in some solid tumours. • Myelosuppression is the major toxicity. IMATINIB • Selective anti-cancer drug whose development was guided by knowledge of specific oncogene • MOA: • specific anticancer drug acts on specific oncogene. • Inhibits tyrosine kinase activity of protein product of B cr-Abl oncogene that is expressed in chronic myelogenous leukemia→ as result proliferation of oncogene inhibited→ apoptosis results. RESISTANCE:• Due to mutation in Bcr-Abl tyrosine kinase PK:• wellabsorbed orally , metabolized in liver , metabolites excreted in faeces through bile. T1/2 – 18 hrs • A/Es- Abdominal pain, vomitting, fluid retention,myalgia and CHF USE: • (1) CML • (2) GI stromal tumors ( C-kit tyrosine kinase) Hormonal therapy Hormonal therapy is one of the major modalities of medical treatment for cancer It involves the manipulation of the endocrine system through exogenous administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones Used for several types of cancers derived from hormonally responsive tissues, including the breast, prostate, endometrium, and adrenal cortex. Most familiar example of hormonal therapy in oncology is the use of the selective estrogen-response modulator tamoxifen for the treatment of breast cancer, although another class of hormonal agents, aromatase inhibitors, now have an expanding role in that disease. Hormones & antagonists Glucocorticoids • Marked lympholytic effect so used in acute leukaemias& lymphomas, • They also – Have Anti-inflammatory effect – Increase appetite, prevent anemia – Produce sense of well being – Increase body weight – Supress hypersensitivity reaction – Control hypercalcemia& bleeding – Non specific antipyretic effect – Increase antiemetic effect of ondansetron Estrogens • Physiological antagonists of androgens • Thus used to antagonize the effects of androgens in androgen dependent prostatic cancer • Fofesterol – Prodrug , phosphate derivative of stilbesterol – 600-1200mg IV initially later 120-240 mg orally Anti-Estrogens • Tamoxifen(SERMs) • Raloxifene(SERMs) • Faslodex Tamoxifen • Selective estrogen receptor modulator (SERM), have both estrogenic and antiestrogenic effects on various tissues • Binds to estrogen receptors (ER) and induces conformational changes in the receptor • Has antiestrogenic effects on breast tissue. • The ability to produce both estrogenic and antiestrogenic affects is most likely due to the interaction with other coactivators or corepressors in the tissue and the binding with different estrogen receptors, ER and ER • Subsequent to tamoxifen ER binding, the expression of estrogen dependent genes is blocked or altered • Resulting in decreased estrogen response. • Most of tamoxifen’s affects occur in the G1 phase of the cell cycle • Toxicity Hot flashes, Fluid retention, nausea Therapeutic Uses • Tamoxifen can be used as primary therapy for metastatic breast cancer in both men and postmenopausal women • Patients with estrogen-receptor (ER) positive tumors are more likely to respond to tamoxifen therapy, while the use of tamoxifen in women with ER negative tumors is still investigational • When used prophylatically, tamoxifen has been shown to decrease the incidence of breast cancer in women who are at high risk for developing the disease Selective Estrogen Receptor Down regulator (fulvestrant) • Pure estrogen antagonist • USES: Metastatic ER+ Breast Ca in postmenopausal women • MOA: • Inhibits ER dimerization & prevents interaction of ER with DNA • ER is down regulated resulting in more complete supression of ER responsive gene function Anti-Androgen 1)) Flutamide – Antagonizes androgenic effects – approved for the treatment of prostate cancer • MOA: bind to androgen receptor inhibit androgen effects. • USE: prostatic carcinoma. • ADR: hot flushes, Hepatic dysfunction, Gynecomastia. 2)) BICALUTAMIDE : • Androgen Receptor antagonists • Palliative effect in metastatic Prostatic Ca Aromatase Inhibitors • Aminogluthethimide • Anastrozole Aminogluthethimide Mechanism of Action • Inhibitor of adrenal steroid synthesis at the first step, conversion of cholesterol of pregnenolone • Inhibits the extra-adrenal synthesis of estrone and estradiol • Inhibits the enzyme aromatase that converts androstenedione to estrone Aminogluthethimide Toxicity • Dizziness, Lethargy, Visual blurring, Rash Therapeutic Uses • ER- and PR-positive metastatic breast cancer AROMATASE INHIBITOR: ANASTRAZOLE: • Inhibit aromatase w/c catalyses conversion of androstenedione (androgenic precursor) to estrone ( estrogenic hormone) • USE: advanced breast cancer • ADR: hot flushes, bone and back pain,Dyspnea • DOSE: 1mg orally daily • Letrozole • Orally active non steroidal compound • MOA : Inhibits aromatisation of testosterone &androstenedione to form estrogen. • Uses : Breast Ca Gonadotropoin-Releasing Hormone Agonists • Leuprolide • Goserelin MOA • Agents act as GnRH agonist, with paradoxic effects on the pituitary • Initially stimulating the release of FSH and LH, followed by inhibition of the release of these hormones • Resulting in reduced testicular androgen synthesis GNRH AGONIST • NAFERELIN : nasal spray / SC inj • ↓FSH & LH release from pituitary-↓ the release of estrogen & testosterone • USE : Breast Ca, Prostatic Ca • PROGESTINS: • Hydroxyprogesterone – used in metastatic endometrial Ca. • A/E: bleeding TOXICITY • Gynecomastia, Edema, thromboembolism USES • Metastatic carcinoma of the prostate • Hormone receptor-positive breast cancer Hormones and related agents – • GLUCORTICOIDS – Prednisolone - most commonly used glucorticoid in Ca.chemo. Used for combination chemotherapy in leukemia and lymphomas • ESTROGEN – Physiological antagonists of androgens Antagonizes the effects of androgens in androgen dependent prostatic tumors- fosfestrol( prodrug) – stilboestrol (prostatic tissue) • TAMOXIFEN- Anti-oestrogen mainly used in the palliative treatment in hormone dependent breast ca • PROGESTINS – Medroxyprogesterone acetate, hydroxyprogesteronecaproate and megestrol 2nd line hormonal therapy for metastatic hormone dependent breast ca and endometrial ca • ANTI-ANDROGENS – Flutamide and bicalutamide – bind to androgen receptor – inhibit androgen actions Prostatic ca, used along with GNRH agonist – strategy known as ‘complete androgen blockade’ Flutamide can cause – hot flushes, hepatic dysfunction and gynaecomastia • GnRH agonists - Goserelin, Nafarelin and leuprolide act as agonist of GnRH used in advanced prostatic ca • GnRHantagonist – Cetrorelix, ganirelix and abarelix are antagonist of GnRH Decrease the release of gonadotropins without causing initial stimulation Can be used in prostatic ca without the risk of flare up reaction • AROMATASE Inhibitors – Anastrozole, letrozoleetc Aromatase is the enzyme responsible for conversion of androstenedione( androgen precursor) to estrone (estrogenic hormone) 1st gen.-aminoglutethimide 2nd gen.-formestane, fadrozole,rogletimide 3rd gen.-exemestane,letrozole,anastrozole Aromatase inhibitors – useful in advanced breast ca. Adverse effects – hot flushes, arthralgia and fatigue