Systems Pharmacology and Chemotherapeutics PDF

Systems Pharmacology and Chemotherapeutics SCPCB3-B44 Eduvos (Pty) Ltd (formerly Pearson Institute of Higher Education) is registered with the Department of Higher Education and Training as a...

Systems Pharmacology and Chemotherapeutics SCPCB3-B44 Eduvos (Pty) Ltd (formerly Pearson Institute of Higher Education) is registered with the Department of Higher Education and Training as a private higher education institution under the Higher Education Act, 101, of 1997. Registration Certificate number: 2001/HE07/008 Lesson 1 Viral host ranges Mammalian viruses  1, Binding to cellular receptors activates cellular transcription factors, 2, The virus then enters the cell, releasing viral DNA, and virion mRNA transcripts which are translated. Viral DNA and certain viral proteins are transported to the nucleus. 3, viral and cellular genes are expressed, and viral DNA is replicated. 4, Viral DNA, viral and cellular proteins, and virion transcripts are packaged into the virion. During egression of the virion from the cell, the virion envelope forms. Life cycle of a generic DNA virus Antiviral drugs Herpes viral infections Respiratory virus Hepatic viral & Cytomegalovirus infections infections infections Amantadine Adefovir Acyclovir Oseltamivir Entecavir Cidofovir Ribavirin Interferon Famciclovir Rimantidine Lamivudine Fomiversin Zanamivir Telbivudine Foscarnet Tenofovir Ganciclovir Penciclovir Valacyclovir Valganciclovir Vidarabin 1) Respiratory virus infections Influenza C viruses Influenza type A and B Respiratory syncytial virus (RSV) Preferred treatment: vaccination Neuraminidase inhibitors (NAI) Oseltamivir, zanamivir Orthomyxoviruses contain the enzyme neuraminidase Catalyse hydrolysis of terminal sialic acid residues For the purpose of releasing newly formed virions Effective against Influenza type A and B Administered prophylactically Does not impair the immune response to the influenza vaccine If administered within the first 24-48 hours of onset Decreases the intensity and duration of symptoms PK & PD Oseltamivir: Oral prodrug Hydrolysed by the liver to its active form Zanamivir: Not orally active Gastrointestinal discomfort Adverse effects: Except for zanamivir Does however cause respiratory tract irritation Resistance Mutations of neuraminidase Adamantine Antivirals Amantadine and rimantadine Interfere with viral M2 proteins (matrix ion channel, beneath coat) Inhibiting the uncoating of and release of viral particles from infected cells Limited to influenza A infections Target early stages of viral infection Treatment & prevention Widespread resistance is a concern Often used in combination with interferon Interferes with viral protein expression PK & PD Adverse effects CNS effects Mild: Insomnia, dizziness, ataxia Severe: Hallucinations, seizures Rimantidine causes fewer CNS AE’s Monitoring required in certain patients Psychiatric problems, renal impairment, epilepsy Gastrointestinal intolerance Resistance In up to 50% of patients Mutations in the M2 matrix protein Cross-resistance: between the two drugs Guanosine analogue Ribavirin Rx: RSV infections in infants & young children Combined with interferon for treatment of: Hepatitis C & Lassa fever Mechanism of action: Drug is converted to ribavirin-triphosphate Inhibits GTP formation Blocking RNA-dependent RNA polymerase Blocking RNA synthesis PK & PD Adverse effects: Dose-dependent transient anaemia Absorption increased with fatty meals Elevated bilirubin Deteriorating respiratory function 2) Hepatic viral infections Hepatitis B and C can cause: Cirrhosis Hepatocellular carcinoma Destruction of hepatocytes Hepatitis B: Peginterferon-α-2a or lamivudine Combination therapy no more effective than lamivudine (PO) monotherapy Hepatitis C: Combination of interferon α (2a or 2b) and ribavirin Interferon indications IFN: targeting early stages of infection 1.Binds cell surface 2.Induces expression of TIP (translation inhibitory protein) 3.TIP binds ribosome, inhibits host expression of viral proteins Interferon Pharmacokinetics: Once a week dosing Intralesionally Subcutaneously Intravenously Interferon Drug interactions Interferons interfere with hepatic drug metabolism Toxic accumulations of theophylline May potentiate the myelosuppression of other drugs E.g. zidovudine Interferon: Adverse effects Flu-like symptoms on injection Fever, chills, myalgias, arthralgias, GIT disturbances Subside with subsequent administration Rare AE’s: Acute hypersensitivity Hepatic failure Dose-limiting toxicities: Severe fatigue Weight loss Autoimmune disorders Thyroiditis Cardiovascular problems CHF Bone marrow suppression Granulocytopenia Neurotoxicity Somnolence & behavioural disturbances Cytosine analogue: Lamivudine Mechanism of action Inhibitor of HBV DNA polymerase & HIV reverse transcriptase Lamivudine is phosphorylated by host cellular enzymes To its active form which then Competitively inhibits DNA polymerase At concentrations that have negligible effects on host DNA polymerase Intracellular t1/2 > plasma t1/2 Widely distributed Renal insufficiency requires dosage reduction AE’s: headache & dizziness Nucleotide analogues Adefovir Phosphorylated to adefovir diphosphate Incorporated into viral DNA Terminates chain elongation & viral replication Entecavir Guanosine analogue Intracellular phosphorylation to the triphosphate Competes with the natural substrate for Viral reverse transcriptase Nucleotide analogues Telbivudine: Thymidine analogue Tenofovir: Acyclic nucleoside phosphonate analogue Hepatitis C virus NS3/4A serine protease inhibitors Boceprevir and telaprevir: PO Direct-acting Must be used in combination (ribavirin & peg-IFN-alpha) Resistance Reversibly bind NS3 protease active site, inhibiting Viral replication Strong inhibitors of CYP3A4/5 3) Herpes Virus Infections HSV-1: orofacial HSV-2: genital herpes Dormancy periods Infectious (outbreak) not fatal, incurable Treatment options: Acyclovir (purine mimic) Cidofovir (pyrimidine mimic) Foscarnet (pyrophoshate) Gancivlovir (purine mimic Strong inhibitors of CYP3A4/5 Acyclovir (ganciclovir) Rx: prophylaxis in seropositive patients Before transplants Acyclovir, MOA Acyclovir: PK& PD Adverse effects Topical administration: local irritation PO: headache, diarrhoea, N&V Transient renal dysfunction In AIDS patients: GIT problems Thrombocytopenia purpura Accumulates in patients with renal failure Acyclovir: PK& PD Resistance Altered or deficient thymidine kinase or DNA polymerase (e.g. cytomegalovirus) Generally in immunocompromised patients Cross-resistance to other cyclovirs occurs Accumulates in patients with renal failure Cidofovir CMV-induced retinitis AIDS patients Less prevalent since HAART Mechanism of action Nucleotide analog of cytosine Phosphorylation not dependent on viral enzymes Inhibits viral DNA synthesis Cidofovir Pharmacokinetics Intravenous, topical & intravitreal administration Slow elimination leads to Extended dosage intervals Cidofovir Adverse effects Nephrotoxicity CI: in patients with pre-existing renal impairment CI: concurrent use of other nephrotoxic drugs Rx: Probenecid AE’s: headache, rash, nausea Neutropenia Metabolic acidosis Ocular hypotony Foscarnet Rx: CMV retinitis, acyclovir-resistant HSV, herpes zoster infection Mechanism of action: Reversibly inhibits viral DNA and RNA polymerase by terminating chain elongation Pharmacokinetics Poorly orally absorbed Frequent dosing intervals Good distribution Foscarnet Adverse effects: Nephrotoxicity Anaemia Nausea Fever Chelation with divalent cations Hypocalcaemia Hypomagnesemia Hypokalaemia Arrhythmias Penciclovir Guanosine nucleoside derivative Rx: HSV-1, HSV-2 and VZV Pharmacokinetics: Topical administration Mechanism of action Monophosphorylated by viral thymidine kinase Inhibits HSV DNA polymerase Famciclovir Analog of 2’-deoxyguanosine It is a prodrug Activated to active penciclovir Adverse effects: Headaches Nausea Experimental animals: Increased incidence of mammary adenocarcinomas & Testicular toxicity Nucleotide vs nucleoside Purine Nucleosides Drugs identified so far: Guanosine: Ribavirin, Famciclovir, Entecavir, Adefovir, Deoxyguanosine: Penciclovir, Acyclovir (Ganciclovir) Pyrimidine nucleosides Drugs identified so far: Thymidine: Telbivudine  HIV/AIDS Antiretrovirals Anti-retrovirals (HIV Tx) HIV infections Abacavir Didanosine Emtricitabine Enfurvitide Efavirenz Indinavir Lamivudine Lopinavir Nevirapine Ritonavir Saquinavir Stavudine Tenofovir Zalcitabine Zidovudine HIV/AIDS HIV/AIDS symptoms Brief flu-like illness 2-4 weeks after infection Swollen lymph nodes Diarrhoea Weight loss Fever Cough & shortness of breath Progression to AIDS symptomsOpportunistic infections Soaking night sweats Shaking chills or fever higher than 38 C for several weeks Cough and shortness of breath Chronic diarrhoea Persistent white spots or unusual lesions on your tongue or in your mouth Headaches Persistent, unexplained fatigue Blurred and distorted vision Weight loss Skin rashes or bumps Life cycle of HIV New viral RNA and The virus matures by Fusion of the HIV cell proteins move to cell protease releasing to the host cell surface and a new, individual HIV surface. immature, HIV virus proteins. forms. HIV RNA, reverse New viral RNA is transcriptase, used as genomic integrase, and other RNA and to make viral proteins enter viral proteins. the host cell. Antiretroviral pharmacology Viral DNA is Viral DNA is formed transported across Antiretroviral by reverse the nucleus and pharmacology transcription. integrates into the host DNA. Treatment options: ARTs antiretrovirals No vaccination Serodiscordant courples Condoms and serotyping PrEP- pre-exposure prophylaxis a pill a day, PO fixed dose combination (FDC) (tenofovir, disoproxil fumarate and emtricitabine) Treatment options: ARTs antiretrovirals HIV test before taking & every 3 months during rx PEP- post exposure prophylaxis- within 3 days daily for 4 weeks (28 days uninterrupted) use triple ARV regimens nevirapine never used for PEP due to side-effects HAART NRTI’s Zidovudine Didanosine Zalcitabine Stavudine Lamivudine Abacavir Tenofovir Emtricitabine NRTI’s Analogs of ribosides (nucleosides or nucleotides containing a ribose) Which all lack a 3’-hydroxyl group Upon entering the cell: they are phosphorylated & Incorporated by reverse transcriptase (viral) into the DNA Lack of a 3’-hydroxyl group Prevents the formation of a 3’-5’ phosphodiester bond Thus chain elongation is terminated NRTI’s Specificity Lower affinity for host DNA polymerase than for HIV transcriptase Although mitochondrial DNA polymerase is susceptible Zidovudine (AZT) Indications: Children Adults Prevents prenatal infection Prophylaxis for exposed individuals Zidovudine (AZT) Mechanism of action Converted to active triphosphate form By thymidine kinase Also inhibits phosphorylation of dTMP to dTDP Required for DNA synthesis Zidovudine Pharmacokinetics Penetrates BBB Food ↓ peak levels of drug Metabolism: glucuronylated in the liver Resistance: Mutations at codons Cross-resistance occurs with other NRTI’s Zidovudine Bone marrow toxicity Anaemia & leukopaenia Headaches Seizures Drug interactions Other glucuronylated drugs: Probenecid, acetaminophen, lorazepam, indomethacin, cimetidine Stavudine & ribavirin  Didanosine Zalcitabine Stavudine Indications Adults & children; HIV-1 Mechanism Missing both 2’ and 3’ =AZT =AZT & inhibits β & γ of action –OH; DNA polymerases: ↓ MOA=AZT mitochondrial DNA synthesis Pharmacoki Acid labile: chewable, Food & Mg2+ or Al2+- Absorption is netics buffered tablets containing antacids ↓ unaffected by food Food ↓absorption absorption Penetrates BBB ↓ Penetrates BBB ↓ Urinary & faecal Clr Adverse Pancreatitis Pancreatitis Peripheral neuropathy effects Dose-limiting: Rash peripheral Stomatitis neuropathy Peripheral neuropathy Buffering interfere CI: Lamivudine absorption CI: Zalcitabine Resistance Reverse transcriptase Point mutations in with AA substitutions reverse transcriptase Cross-resistance  Lamivudine Abacavir Tenofovir Emtricitabine MOA =AZT & inhibits Guanosine Analog of Derivative of reverse analog adenosine-5’- lamivudine transcriptase mono-phosphate Inhibits reverse Doesn’t affect Converts to transcriptase mitochondria diphosphate & inhibits HIV reverse transcriptase PK Oral Oral Food increases Oral Renal excretion absorption Once-a-day dosing CI: Zalcitabine Urinary excretion AEs Well-tolerated GIT Nausea GIT, Rash Headache Diarrhoea Hyper- Malaise Vomiting Pigmentation of Rash soles & palms Dizziness Hepato-megaly Lactic acidosis Fatty liver Resist Mutation at viral Cross Cross resistance -ance codon 184 which resistance also restores with AZT & NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Nevirapine Delavirdine Efavirenz Etravirine NNRTI’s Highly selective, non- competitive inhibitors That results in enzyme of HIV-1 reverse inhibition transcriptase Bind to enzyme at a Inducing a site adjacent to the conformational change active site Nevirapine Indication Used in combination with other ARV’s Resistance develops rapidly with monotherapy For HIV-1 treatment in adults and children Prevention of mother to child transmission of HIV/AIDS Nevirapine Pharmacokinetics Well absorbed orally Absorption is not affected by food and antacids Good distribution: CNS, foetus & breast milk Excretion: urine As glucuronides of hydroxylated metabolites Nevirapine: AEs Common: rash, fever, headache, elevated serum transaminases Severe dermatological conditions: 1.Steven Johnson’s syndrome 2.Toxic epidermal necrolysis Hepatotoxicity Nevirapine: AEs Drug interactions: Inducer of CYP3A4 Oral contraceptives, warfarin, ketoconazole, quinidine, theophylline, PIs (?) No dosage adjustments required with concomitant administration of NRTI’s Nevirapine: AEs Toxic epidermal drug-induced necrolysis 14-day titration period (1/2 dose) reduce risk  Delavirdine Efavirenz PK Oral Oral Unaffected by food Good distribution Extensively plasma protein Absorption ↑ with high fat meals bound Extensively plasma protein bound Feaces:urine excr (50:50) Once-daily dosing Adverse effects Common: rash CNS: headache, dizziness, vivid Nausea, dizziness, headache dreams, lack of concentration Inhibitor of CYP450 Usually resolve within a few weeks Saquinavir & indinavir Rash:25% Fluoxetine & ketoconazole Modest inducer of CYP450 ↑[delavirdine] Dose of indinavir may need to be increased when given with Phenytoin&phenobarbital efavirenz Decrease [delavirdine] Actions Increases CD4 count Decreases viral load HIV PROTEASE INHIBITORS Saquinavir Ritonavir Indinavir Reversible Than for human = selective toxicity inhibitor of proteases Nelfinavir Amprenavir These inhibitors Prevents Lopinavir HIV aspartyl show a 1000x maturation of the protease greater affinity for viral particles & HIV proteases Atazanavir Darunavir Results in the Viral polyprotein Responsible for production of into enzymes & Fosamprenavir the cleavage of non-infectious structural proteins virions Tipranavir PI’s Saquinavir Used in combination with other drugs (NRTI’s) Ritonavir Pharmacokinetics Indinavir Nelfinavir Poor oral bioavailability Amprenavir High fat meals affect bioavailability Lopinavir Increased: nelfinavir & saquinavir Atazanavir Decreased: indinavir Darunavir Dosage adjustment: unnecessary in renal failure Fosamprenavir Substrate for P-glycoprotein efflux pump Tipranavir Limits access to CNS PI’s: Adverse effects Common: paraesthesia, nausea, vomiting, diarrhoea Saquinavir Ritonavir Disturbances in lipid & glucose metabolism Indinavir Diabetes Nelfinavir Hypertriacylglycerolaemia Amprenavir Hypercholesterolaemia Lopinavir Atazanavir Chronic administration: Darunavir results in fat redistribution Fosamprenavir Fat loss in extremities Tipranavir Accumulation in the abdomen and base of the neck: “buffalo hump” Breast enlargement PI’s Resistance Stepwise mutations in the protease gene Initially: decreased ability of the virus to replicate Then: virions with high levels of resistance emerge PI’s Drug interactions PI’s are CYP450 inhibitors Ritonavir: most potent Saquinavir: least potent Examples: Midazolam: excessive sedation Fentanyl: respiratory depression Warfarin: excessive bleeding Inducers of CYP450 will decrease [PI]  Saquinavir Ritonavir Indinavir Pharmacokinetics Soft-gel capsule 60% bioavailabiltiy Combination with formation: lowest Unaffected by food reverse transcriptase amount absorbed of Unpalatable inhibitors: sustained all protease inhibitors “Pharmacokinetic effects Bioavailability enhancer” Least protein bound improves if given with Also self-inducer of Acidic gastric ritonavir own metabolism conditions necessary Multiple daily doses: for absorption or given in Shortest half-life combination with delavirdine  Nelfinavir Amprenavir Lopinavir Atazanavir Pharmaco- Doesn’t require Twice-daily Rx: patients Food increases its kinetics strict food or fluid dosing unresponsive to absorption restrictions Coadmini-stration other PI’s Highly plasma CYP2C19 of ritonavir: Poor intrinsic protein bound Can inhibit the Increases bioavailability CYP3A4 metabolism of [amprenavir] Addition of metabolism other drugs ritonavir Competitive Oral solution inhibitor of contains alcohol: glucoronyl causes tranfersase unpleasant Prolongs the PR effects with interval & slows disulphiram heart rate Contra-indicated medications Viral Entry Inhibitors PI’s Enfuvirtide Maraviroc Enfuvirtide In order for HIV to It must fuse its With that of the gain entry: membrane host cell Changes in conformation of Preventing the Enfuvirtide binds gp41 when the conformational to gp41 HIV binds to the change host cell surface Enfuvirtide Indication: Combined with other ARVs Treatment-experienced individuals with evidence of viral replication despite other therapies Adverse effects: Injection related: pain, erythema, nodules Expensive medication Maraviroc Mechanism of action To facilitate Inhibits the HIV entry Indication: That assists CCR5 co- through the GP41 R5 virus receptor membrane wall Dosage adjustment: Dosage reduced when given in conjunction with PI’s Dosage increased when given in conjunction with NNRTI’s Integrase Inhibitors Raltegravir Mechanism of action After reverse transcription of viral RNA into DNA HIV DNA must be inserted into the host cell’s DNA Integrase inhibitors prevent this Raltegravir Adverse effects: Less serious: Nausea, headache, diarrhoea Elevated creatine kinase Muscle pain Rhabdomyolysis Depression Suicidal ideation Mnemonic antiretrovirals Mnemonic antiretrovirals Prevention of mother-to-child transmission (PMTCT)  PMTCT AZT? NVP? 3TC? FP: family planning PMTCT CTC: Centres for disease control PMTCT  Cancer Lesson 2 Chemotherapy What makes a cell divide uncontrollably? Three methods of treating cancer Three methods of treating cancer Principles of cancer chemotherapy Chemotherapy can arrest a tumour’s progression Directed against metabolic sites Essential to cell replication Problem: SPECIFICITY The drugs affect all proliferating cells Both normal and cancerous NB: dose response curve  Antineoplastics: Affect all cells undergoing rapid proliferation cells of the buccal mucosa, bone marrow, gastrointestinal [GI] mucosa, and hair follicles) Managing side effects of chemotherapy Managing side effects of chemotherapy Principles of cancer chemotherapy A. Treatment strategies Goals of treatment: disease free survival Debulked (surgery/radiation), chemotherapy, immunotherapy Indications for treatment Disseminated (surgery not an option) Supplemental treatment Tumour susceptibility and growth cycle 1. Cell-cycle specificity of drugs 2. Tumour growth rate Palliative Care (Palliation) “to relieve or lessen without curing; mitigate; alleviate. 2. to try to mitigate or conceal the gravity of (an offense) by excuses, apologies, etc.; extenuate. Origin of palliate. Late Latin” Principles of cancer chemotherapy B. Treatment regimens and scheduling: Administered on BSA – tailor medications Log kill First-order kinetics: constant fraction of cells destroyed Five-log kill = remission Pharmacologic sanctuaries CNS: BBB Solid tumours Principles of cancer chemotherapy B. Treatment regimens and scheduling: Treatment protocols 1. Combinations of drugs: different toxicities, MOA’s & different sites 2. Advantages of drug: combinations Provides maximal cell killing within the range of tolerated toxicity Effective against a broader range of cell lines May delay or prevent the development of resistant cell lines 3. Treatment protocols: intermittent therapy Problems associated with chemotherapy Resistance Melanoma: inherently resistant Mutations: after prolonged low doses Minimised by intensive, short-term intermittent combination therapy Problems associated with chemotherapy Multidrug resistance P-glycoprotein: ATP-dependent pumping of drugs out of the cell Highly expressed: kidney, liver, pancreas, small intestine, colon, adrenal gland Cross-resistance between structurally-unrelated drugs Problems associated with chemotherapy Toxicity A. Common adverse effects: Narrow therapeutic index B. Minimising adverse effects Treatment-induced tumours Anticancer drugs Visual Mnemonic on drug Antimetabolites examples Antibiotics Alkylating agents Microtubule inhibitors Steroid hormones and their antagonists Monoclonal antibodies Others Anticancer drugs Microtubule Antimetabolites Antibiotics Alkylating agents inhibitors Capecitabine Bleomycin Busulfan Docetaxel Cladribine Dactinomycin Carmustine Paclitaxel Cytarabine Daunorubicin Chlorambucil Vinblastine Fludarabine Doxorubicin Cyclophospha- Vincristine 5-Fluorouracil Epirubicin mide Vinorelbine Gemcitabine Idarubicin Dacarbazine 6- Nosfamide Mercaptopurine Lomustine Methotrexate Mechlorethamin 6-Thioguanine e Melphalan Streptozocin Temozolomide Anticancer drugs Steroid hormones and their Monoclonal antibodies Others antagonists Aminoglutethimide Bevacizumab Asparaginase Anastrozole Cetuximab Cisplatin Bicalutamide Rituximab Carboplatin Exemestane Trastuzumab Etoposide Flutamide Gefitinib Goserelin Imatinib Letrozole Interferons Leuprolide Irinotecan Megestrol acetate Oxaliplatin Nilutamide Procarbazine Oestrogen Topotecan Prednisone Tamoxifen Toremifene Antimetabolites ANTIMETABOLITES Antimetabolites are structurally related to normal ANTIBIOTICS compounds of the cell ALKYLATING They interfere with the availability of AGENTS Normal purine or MICROTUBULE INHIBITORS Normal pyrimidine nucleotide precursors STEROIDS HS AND ANTAGONISTS Either by inhibiting their synthesis or by Competing with them in DNA or RNA synthesis MONOCLONAL ANTIBODIES Cytotoxic effects: S-phase specific OTHERS Nucleotide biosynthesis Nucleotide biosynthesis video Methotrexate ANTIMETABOLITES Methotrexate = structurally related to folic acid ANTIBIOTICS Acts as an antagonist of folic acid ALKYLATING AGENTS By inhibiting dihydrofolate reductase MICROTUBULE Enzyme that converts folic acid to its active INHIBITORS tetrahydrofolate form STEROIDS HS AND ANTAGONISTS Close monitoring required MONOCLONAL ANTIBODIES OTHERS Mechanism of action: Methotrexate Resistance Non-proliferating cells 1. Lack of: DHFR Thymidylate synthase Glutamylating enzyme 2. Decreased enzyme affinity for MTX Mechanism of action: Methotrexate 2. Reduced influx of MTX Therapeutic indications ALL Burkitt lymphoma, Breast cancer Head and neck carcinomas Inflammatory diseases: psoriasis, RA, Crohn disease Pharmacokinetics: Methotrexate Intrathecal administration: central sanctuary sites Fate: Metabolism to polyglutamate derivatives Also inhibit DHFR 7-OH derivative is much less active Less water soluble Crystalluria Prevention: Keep urine alkaline & Ensure adequate hydration Methotrexate: Adverse effects Commonly observed toxicities Nausea, vomiting, diarrhoea Stomatitis, myelosuppression, erythema, urticaria, rash, alopaecia Rx: administration of leucovorin Taken up more readily by normal cells than tumour cells Methotrexate: Adverse effects Renal damage High dose MTX Rx: alkalinisation of urine Hepatic function Long term use: fibrosis or cirrhosis Methotrexate: Adverse effects Pulmonary toxicity Reversible Children: cough, dyspnea, fever, cyanosis Neurologic toxicities Intrathecal administration: stiff neck, headache, fever, seizures, encephalopathy, paraplegia Contraindications Abortifacient 6-Mercaptopurine ANTIMETABOLITES ANTIBIOTICS Thiol analog of hypoxanthine Indication: ALL ALKYLATING AGENTS Mechanism of action MICROTUBULE INHIBITORS 1. Nucleotide formation STEROIDS HS AND Converted to 6-mercaptopurine-ribose- ANTAGONISTS phosphate MONOCLONAL 6-thioinosinic acid (TIMP) ANTIBODIES Addition of this nucleotide: HGPRT OTHERS 6-Mercaptopurine ANTIMETABOLITES ANTIBIOTICS 2. Inhibition of purine synthesis ALKYLATING AGENTS 3. Incorporation into nucleic acids Incorporated after phosphorylation MICROTUBULE INHIBITORS Into RNA and DNA STEROIDS HS AND ANTAGONISTS Non-functional MONOCLONAL ANTIBODIES OTHERS  Mechanism of action: 6-Mercaptopurine Resistance 1. Inability to transform 6-MP to corresponding nucleotide Because of decreased levels of HGPRT Lesch-Nyan syndrome 2. An increased dephosphorylation 3. Increased metabolism of the drug  Mechanism of action: 6-Mercaptopurine Adverse effects Bone marrow depression Nausea, vomiting, diarrhoea Hepatotoxicity Pharmacokinetics: 6-Mercaptopurine Erratic oral absorption 6-MP broken down to Thioruric acid By xanthine oxidase Allopurinol often used in cancer to reduce hyperuricaemia Xanthine oxidase inhibitor May require dosage reduction of 6-MP Structural similarity between Allopurinol and hypoxanthine (6-Mercaptopurine)  6-Thioguanine ANTIMETABOLITES Purine analog ANTIBIOTICS Converted to the nucleotide form ALKYLATING AGENTS Can be incorporated into RNA and DNA MICROTUBULE Inhibits biosynthesis of the purine ring & INHIBITORS Inhibits the phosphorylation of GMP to GDP STEROIDS HS AND ANTAGONISTS Cross-resistance MONOCLONAL ANTIBODIES 6-MP and 6-TG Similar toxicities to 6-MP OTHERS Fludarabine & Cladribine ANTIMETABOLITES Purine nucleotide analog ANTIBIOTICS Prodrug ALKYLATING Phosphorylated & incorporated into DNA and RNA AGENTS Decreases their synthesis in the S-phase MICROTUBULE INHIBITORS Indication: CLL Hairy cell leukaemia STEROIDS HS AND ANTAGONISTS Non-hodgkins lymphoma MONOCLONAL Pharmacokinetics ANTIBODIES IV administration OTHERS Intestinal bacteria convert fludarabine to toxic fluoroadenine Fludarabine & Cladrabine Nausea, vomiting, diarrhoea, myelosuppression Adverse effects Dose-limiting toxicities Fever Oedema Severe neurological toxicity At high doses: Encephalopathy, blindness, death 5-Fluorouracil Pyrimidine analog Stable fluorine atom (position 5 of the uracil ring) Interferes with the conversion of deoxyuridylic acid to thymidylic acid Depriving the cell of one of the essential precursors for DNA synthesis 5-Fluorouracil Indications Slowly-growing solid tumours Colorectal, breast, ovarian, pancreatic & gastric carcinomas Superficial basal cell carcinomas: applied topically Adjuvant therapy: Levamisole: colon cancer  ANTIMETABOLITES ANTIBIOTICS Mechanism of ALKYLATING AGENTS action: MICROTUBULE INHIBITORS 5-Fluorouracil STEROIDS HS AND ANTAGONISTS MONOCLONAL ANTIBODIES OTHERS Pharmacokinetics: Fluorouracil Severe toxicity to GIT: IV administration Or topical administration Metabolism: Converted to fluoro-β-alanine & CO2 Hepatic dysfunction: dosage adjustment Fluorouracil ANTIMETABOLITES Resistance: ANTIBIOTICS Cells that have lost the ability to convert 5-FU to ALKYLATING AGENTS its active form Altered or increased thymidylate synthase MICROTUBULE INHIBITORS Increased rate of 5-FU catabolism STEROIDS HS AND ANTAGONISTS Elevated levels of dihydopyrimidine dehydrogenase MONOCLONAL ANTIBODIES Decreases the availability of 5-FU OTHERS Fluorouracil ANTIMETABOLITES ANTIBIOTICS Adverse effects ALKYLATING N&V, diarrhoea, alopaecia, myelosuppression, AGENTS anorexia MICROTUBULE Severe ulceration of gastric mucosa INHIBITORS “Hand-foot syndrome”: dermopathy STEROIDS HS AND ANTAGONISTS MONOCLONAL ANTIBODIES OTHERS Palmar-Plantar Erythrodysesthesia Capecitabine Indications: Resistant metastatic breast cancer Resistant to first-line drugs Paclitaxel & anthracyclines Mechanism of action Hydrolysis to 5-FU Catalysed by thymidine phosphorylase Concentrated mainly in tumours Tumour-specificity 5-FU: Inhibits thymidylate synthase Capecitabine ANTIMETABOLITES Pharmacokinetics ANTIBIOTICS Oral administration: well absorbed ALKYLATING AGENTS Adverse effects MICROTUBULE Similar to 5-FU INHIBITORS Cautious use in renal & hepatic dysfunction STEROIDS HS AND ANTAGONISTS CI: Patients hypersensitive to 5-FU MONOCLONAL Pregnant/lactating women ANTIBODIES Coagulation parameter monitoring: OTHERS Patients taking coumarin anticoagulants Cytarabine (Ara-C) ANTIMETABOLITES Analog of 2’deoxycytidine ANTIBIOTICS Ara-C acts as a pyrimidine antagonist ALKYLATING AGENTS Indication: MICROTUBULE INHIBITORS AML: in combination with 6-TG & daunorubicin Mechanism of action STEROIDS HS AND ANTAGONISTS Phosphorylated to nucleotide form MONOCLONAL ANTIBODIES Incorporated into DNA Decreases chain elongation-> S-phase specific OTHERS Pharmacokinetics: Cytarabine Oral administration: deamination to ara-U Inactive metabolite Thus IV and intrathecal administration Resistance Defect in transport process Change in phosphorylating enzymes Increased natural dCTP nucleotide Increased deamination to Ara-U Pharmacokinetics: Cytarabine Adverse effects Nausea, vomiting, diarrhoea, myelosuppression Hepatic dysfunction High doses/intrathecal administration: Seizures or altered mental states Gemcitabine ANTIMETABOLITES ANTIBIOTICS Analog of the nucleoside deoxycytidine ALKYLATING AGENTS Indications: MICROTUBULE Locally advanced or INHIBITORS metastatic adenocarcinoma of the STEROIDS HS AND ANTAGONISTS pancreas MONOCLONAL Lung cancer ANTIBODIES OTHERS Gemcitabine Resistance Alteration in deoxycytidine Inability to be converted to a nucleotide Tumour cell can produce increased levels of deoxycytidine Pharmacokinetics IV administration Deaminated to difluorodeoxyuridine: not cytotoxic Gemcitabine Adverse effects Myelosuppression: dose-limiting toxicity Nausea, vomiting, diarrhoea, alopaecia, rash, flu-like syndrome Transient elevations: serum transaminases Proteinuria, haematuria Daunoblastin Dactinomycin ANTIMETABOLITES ANTIBIOTICS Indications ALKYLATING AGENTS Wilm’s tumour MICROTUBULE INHIBITORS In combination with surgery & vincristine Soft tissue sarcomas STEROIDS HS AND ANTAGONISTS MONOCLONAL ANTIBODIES OTHERS Dactinomycin ANTIMETABOLITES ANTIBIOTICS Mechanism of action Dactinomycin intercalates into the minor groove of the ALKYLATING AGENTS Double helix between guanine-cytosine pairs of DNA MICROTUBULE INHIBITORS Forming a stable dactinomycin-DNA complex STEROIDS HS AND And interferes with DNA-dependant RNA polymerase ANTAGONISTS And interferes with DNA synthesis MONOCLONAL ANTIBODIES Also causes single strand breaks OTHERS Due to action on topoisomerase II Dactinomycin ANTIMETABOLITES ANTIBIOTICS Resistance: P-glycoprotein mediated efflux ALKYLATING AGENTS Adverse Effects: MICROTUBULE Bone marrow depression INHIBITORS Immunosuppression Nausea, vomiting, diarrhoea, STEROIDS HS AND ANTAGONISTS stomatitis, alopaecia Sensitises to radiation MONOCLONAL ANTIBODIES Inflammation at sites of prior radiation therapy may OTHERS occur  ANTIMETABOLITES Doxorubicin & daunorubicin ANTIBIOTICS Anthracycline antibiotics ALKYLATING Doxorubicin is the hydroxylated form of AGENTS daunorubicin MICROTUBULE INHIBITORS Also: idarubicin & epirubicin Indications: STEROIDS HS AND ANTAGONISTS Doxorubicin: sarcomas, carcinomas, ALL, MONOCLONAL lymphomas ANTIBODIES Daunorubicin & idarubicin: acute leukaemias OTHERS Mechanism of action: Doxorubicin & daunorubicin Intercalation in the DNA Drugs insert themselves between base pairs and bind to the sugar phosphate backbone of the DNA Causing uncoiling Blocking DNA & RNA synthesis Intercalation interferes with topoisomerase II Causing irreparable breaks Binding to cell membranes Alters the function of transport processes Coupled to phosphatidylinositol activation Generation of oxygen radicals Free radicals reduce molecular oxygen Producing superoxide ions and hydrogen peroxide Mediate strand scission of DNA Protection: glutathione peroxidase & superoxide dismutase Cardiac tissue & tumours: low in SOD Cardiac tissue lacks catalase: cardiotoxicity??? Pharmacokinetics: Doxorubicin & daunorubicin Inactivation in GIT: IV administration Extravasation can lead to tissue necrosis Excretion: Bile Urine (red colour) Adverse Effects GIT upset, transient bone marrow suppression, stomatitis, Severe alopaecia, Skin pigmentation Irreversible, dose-dependant cardiotoxicity (daunorubicin> doxorubicin) Rx: dexrasone (iron chelator) protects against cardiotoxicity Doxorubicin extravasation Bleomycin ANTIMETABOLITES Mixture of different copper chelating glycopeptides ANTIBIOTICS Cause scission of DNA by an oxidative process ALKYLATING AGENTS Causes cells to accumulate in G2 phase MICROTUBULE Indications: INHIBITORS Testicular tumours: in combination with vinblastine or STEROIDS HS AND etoposide ANTAGONISTS Cisplatin improves response rate MONOCLONAL ANTIBODIES Squamous cell carcinomas OTHERS Lymphomas Bleomycin Resistance Increased efflux of the drug oxidation Presence of bleomycin hydrolase Which inactivates bleomycin & Is found in [high] in the liver & spleen But is in [low] in skin & lungs Pharmacokinetics: SC, IV, IM & intracavitary Dosage adjustment: renal failure Bleomycin Adverse reactions: Pulmonary toxicity: (Cough & infiltrates) oxidation Mucocutaneous reactions & alopaecia Hypertrophic skin changes & skin pigmentation High incidence: fever & chills Low incidence: analphylactoid reactions Rare: myelosuppression!!! Alkylating agents Form covalent bonds with certain cellular constituents Alkylation with DNA Most toxic for rapidly dividing cells Used in combination with a wide range of other drugs Can lead to secondary malignancies Milton Winternitz came to E.g. Acute leukaemia Yale as chair of pathology in 1917 Mechlorethamine Nitrogen mustard: WWII Indications: Hodgkin’s lymphoma Resistance Decreased permeability of the drug Increased conjugation with glutathione Increased DNA repair http://medicalpicturesinfo.com/hodgkin%E2%80%99s- disease/ Pharmacokinetics Unstable drug Powerful vesicant - IV administration only Mechlorethamine Transported into the cell Alkylates the N7 of guanine On one or both DNA strands Cross-linking Facilitates DNA strand breakage Can also cause miscoding mutations Cell-cycle non-specific Can occur in resting and actively dividing cells But proliferating cells are more sensitive to this drug Mechlorethamine Adverse events: Severe N&V, pretreat palonosetron & dexamethasone Severe bone marrow depression, Limits use Due to immunosuppression: latent viral infections Extravasation Rx: isotonic sodium thiosulfite Cyclophosphamide & ifosfamide Mustard agents But CAN be taken ORALLY Cytotoxic only after generation of alkylating species Produced through hydroxylation by CYP450 Broad clinical spectrum Indications Burkitt lymphoma Breast cancer Nephrotic syndrome Intractable RA Cyclophosphamide & ifosfamide Mechanism of action Biotransformation: CYP450 Hydroxylated intermediates undergo breakdown to form active components Phosphoramide, mustard, acrolein Reaction with DNA = cytotoxic Resistance Increased DNA repair Decreased drug permeability Reaction of the drug with thiols Glutathione Adverse effects: Cyclophosphamide & ifosfamide Nausea, vomiting, diarrhoea, alopaecia Bone marrow depression Haemorrhagic cystitis Can lead to fibrosis of the bladder Acrolein? Rx: adequate hydration & IV sodium-2-mercaptoethane sulfonate Amenorrhoea, testicular atrophy, sterility Veno-occlusive disease: 25% of patients Neurotoxicity Secondary malignancies Nitrosoureas ANTIMETABOLITES Examples: carmustine, lomustine & streptozocin ANTIBIOTICS Indications: ALKYLATING Penetrate CNS: brain tumours AGENTS Mechanism of action: MICROTUBULE INHIBITORS Alkylation that cross-links strands of DNA Preventing replication & STEROIDS HS AND ANTAGONISTS RNA and protein synthesis MONOCLONAL Cytotoxicity is expressed only on cell division ANTIBODIES Non-dividing cells can escape cell death OTHERS If DNA repair occurs Nitrosureas ANTIMETABOLITES ANTIBIOTICS Pharmacokinetics Carmustine: IV administration ALKYLATING AGENTS Lomustine: oral administration Distribution MICROTUBULE INHIBITORS Lipophilic Penetrates CNS STEROIDS HS AND ANTAGONISTS Resistance DNA repair MONOCLONAL Reaction with thiols ANTIBODIES OTHERS Adverse effects: Nitrosureas Delayed haematopoietic suppression Aplastic marrow: prolonged use Renal toxicity Pulmonary fibrosis Streptozocin: diabetogenic Other alkylating agents ANTIMETABOLITES ANTIBIOTICS ALKYLATING AGENTS MICROTUBULE INHIBITORS Temozolamide & dacarbazine Treatment-resistant gliomas and anaplastic STEROIDS HS AND ANTAGONISTS astrocytomas MONOCLONAL Melanoma ANTIBODIES Melphalan OTHERS Other alkylating agents ANTIMETABOLITES ANTIBIOTICS Chlorambucil ALKYLATING CLL AGENTS AE’s: haematological toxicities, GIT upsets MICROTUBULE INHIBITORS Busulfan STEROIDS HS AND ANTAGONISTS Chronic granulocytic leukaemia AE’s: myelosuppression, pulmonary fibrosis, MONOCLONAL ANTIBODIES leukemogenic OTHERS Microtubule inhibitors ANTIMETABOLITES Mitotic spindle: part of cytoskeleton ANTIBIOTICS Essential for the movements of structures ALKYLATING AGENTS Occurring in the cytoplasm of all cells MICROTUBULE Mitotic spindle INHIBITORS Chromatin STEROIDS HS AND ANTAGONISTS System of microtubules MONOCLONAL Composed of tubulin protein ANTIBODIES Function: equal partitioning of DNA into two daughter cells OTHERS Microtubule inhibitors disrupt this process Vinca alkaloids Examples: vincristine, vinblastine & vinorelbine Vincristine ALL Wilm’s tumour Ewing soft tumour sarcoma Hodgkin & Non-Hodgkins lymphoma Vinblastin & bleomycin & cisplatin Metastatic testicular carcinoma Hodgkin & Non-Hodgkins lymphoma Vinorelbine: non-small cell lung cancer Vinca alkaloids ANTIMETABOLITES Mechanism of action: ANTIBIOTICS Cell-cycle and phase-specific: metaphase ALKYLATING AGENTS Bind to microtubular protein: tubulin GTP-dependent MICROTUBULE INHIBITORS Blocks the ability of tubulin to polymerise to form microtubules STEROIDS HS AND Thus alkaloid & tubulin complexes are formed ANTAGONISTS Prevents chromosomal segregation & cell proliferation MONOCLONAL ANTIBODIES Resistance Enhanced efflux OTHERS Alterations in tubulin structure: affecting binding Mechanism of action Vinca alkaloids ANTIMETABOLITES Adverse effects: ANTIBIOTICS Phlebitis & cellulitis: With drug extravasation ALKYLATING AGENTS Nausea, vomiting, diarrhoea, alopaecia MICROTUBULE Vinblastine: more potent myelosuppressor INHIBITORS Vincristine: peripheral neuropathy, constipation, STEROIDS HS AND inappropriate ADH secretion ANTAGONISTS Vinorelbine: granulocytopaenia MONOCLONAL ANTIBODIES Anticonvulsants can accelerate their metabolism OTHERS Azole antifungals can slow its metabolism Taxanes: paclitaxel & docetaxel ANTIMETABOLITES Paclitaxel ANTIBIOTICS Ovarian cancer, Metastatic breast cancer ALKYLATING Paclitaxel & cisplatin: lung cancer AGENTS Docetaxel: more potent, fewer side effects MICROTUBULE INHIBITORS Chromosome Which are non- G2/M phase segregation STEROIDS HS AND functional doesn’t occur ANTAGONISTS Reversibly bind Forms overly Results in to β-tubulin stable MONOCLONAL death of cell subunit microtubules ANTIBODIES Promote Unlike vinca polymerisation alkaloids: and stability of OTHERS the polymer Taxanes Resistance Amplified P-glycoprotein ANTIMETABOLITES Pharmacokinetics ANTIBIOTICS expression Large volume of distribution Mutation in tubulin ALKYLATING AGENTS Do not cross BBB structure MICROTUBULE Elimination: faeces INHIBITORS Doesn’t require dosage STEROIDS HS AND ANTAGONISTS adjustment in renal failure Does require dosage MONOCLONAL ANTIBODIES reduction in hepatic dysfunction OTHERS Taxanes ANTIMETABOLITES ANTIBIOTICS Adverse effects: Dose-limiting toxicity: neutropaenia Rx: filgrastim (G-CSF) ALKYLATING AGENTS Peripheral neuropathy Transient ischaemic bradycardia (Paclitaxel) MICROTUBULE INHIBITORS Fluid retention (Docetaxel) Contraindicated in heart disease STEROIDS HS AND Hyperuricaemia ANTAGONISTS Alopaecia Uncommon vomiting and diarrhoea MONOCLONAL ANTIBODIES Serious hypersensitivity reactions Dyspnea, urticaria, hypotension ‒Pretreatment: dexamethasone OTHERS & diphenhydramine Steroid hormones and ANTIMETABOLITES antagonists ANTIBIOTICS Hormone responsive tumours→ Rx w/ hormone ALKYLATING AGENTS OR MICROTUBULE INHIBITORS Hormone dependent → Rx w/ antagonist OR STEROIDS HS AND ANTAGONISTS Both?? MONOCLONAL ANTIBODIES Where are the hormone receptors located? OTHERS Prednisone ANTIMETABOLITES ANTIBIOTICS Indications: Lymphoma ALKYLATING Mechanism of action AGENTS Prednisone is reduced to active prednisolone MICROTUBULE INHIBITORS By 11-β-hydroxysteroid dehydrogenase Steroid binds to a receptor STEROIDS HS AND ANTAGONISTS Triggers the production of certain proteins MONOCLONAL ANTIBODIES Resistance Absence/mutation of receptors OTHERS ANTIMETABOLITES ANTIBIOTICS ALKYLATING AGENTS MICROTUBULE INHIBITORS STEROIDS HS AND ANTAGONISTS MONOCLONAL ANTIBODIES OTHERS Prednisone ANTIMETABOLITES ANTIBIOTICS Pharmacokinetics Oral administration ALKYLATING AGENTS Highly plasma-protein bound MICROTUBULE INHIBITORS Prednisolone: glucuronidated & excreted in urine STEROIDS HS AND ANTAGONISTS MONOCLONAL ANTIBODIES OTHERS Prednisone ANTIMETABOLITES Adverse effects: ANTIBIOTICS Immunosuppressant ALKYLATING Predispose patients to infection AGENTS Hyperglycaemia MICROTUBULE INHIBITORS Cataract formation STEROIDS HS AND Glaucoma ANTAGONISTS Osteoporosis MONOCLONAL ANTIBODIES Behavioural changes OTHERS Euphoria or psychosis Tamoxifen Oestrogen agonist/antagonist Classified as SERM ANTIMETABOLITES ANTIBIOTICS First-line therapy: oestrogen receptor-positive breast cancer ALKYLATING Prophylaxis: high risk breast cancer AGENTS Mechanism of action: MICROTUBULE INHIBITORS Tamoxifen binds to oestrogen receptor Non-productive complex STEROIDS HS AND ANTAGONISTS Tamoxifen competes with oestrogen MONOCLONAL ANTIBODIES Administered with leuprolide: lowers oestrogen levels No oestrogen-responsive RNA synthesis OTHERS Results in depletion of oestrogen receptors Tamoxifen Resistance Decreased affinity for receptor Dysfunctional receptors Adverse effects: Hot flashes, nausea, vomiting, skin rashes, vaginal bleeding & discharge Similar to natural oestrogen activity Potential to cause endometrial cancer Hypercalcaemia: upon cessation of drug Thromboembolism Affects vision Aromatase inhibitors Aminoglutethimide Anastrozole & letrozole Exemestane Aromatase inhibitors ANTIMETABOLITES Aromatase reaction: ANTIBIOTICS Responsible for extra-adrenal synthesis of oestrogen ALKYLATING from androstenedione AGENTS Takes place in: liver, fat, muscle, skin tissue & breast MICROTUBULE tissue INHIBITORS Peripheral aromatisation STEROIDS HS AND ANTAGONISTS Important source of oestrogen in post-menopausal women MONOCLONAL ANTIBODIES Aromatase inhibitors mechanism of action: OTHERS Decrease the production of oestrogen Aminoglutethimide ANTIMETABOLITES Rx: metastatic breast cancer ANTIBIOTICS Mechanism of action: ALKYLATING Inhibits adrenal synthesis of pregnenolone from AGENTS cholesterol MICROTUBULE Precursor of oestrogen INHIBITORS Also inhibits hydrocortisone synthesis STEROIDS HS AND ANTAGONISTS Causes a compensatory rise in ACTH Thus generally administered with hydrocortisone MONOCLONAL ANTIBODIES Non-selective properties OTHERS Development of new aromatase inhibitors Anastrozole & letrozole Non-steroidal Oral administration Cause an almost total suppression of oestrogen synthesis Advantages in the treatment of breast cancer: More potent More selective No need for supplementation with hydrocortisone Do not predispose patients to endometrial cancer Do not have androgenic side effects Progestins ANTIMETABOLITES ANTIBIOTICS Example: megestrol acetate Indications: ALKYLATING AGENTS Metastatic hormone-responsive MICROTUBULE breast and endometrial cancer INHIBITORS Mostly replaced by aromatase inhibitors STEROIDS HS AND ANTAGONISTS MONOCLONAL ANTIBODIES OTHERS Leuprolide & goserelin ANTIMETABOLITES GnRH: normally secreted by the hypothalamus ANTIBIOTICS Stimulates the anterior pituitary to secrete gonadotropic ALKYLATING hormones: AGENTS LH: stimulates secretion of testosterone MICROTUBULE INHIBITORS FSH: stimulates secretion of oestrogen Mechanism of action (Leuprolife, goserelin, triptorelin) STEROIDS HS AND ANTAGONISTS Desensitises the GnRH receptors in the pituitary MONOCLONAL Causing decreased release of LH & FSH ANTIBODIES Causing less androgen & oestrogen secretion OTHERS Leuprolide & goserelin ANTIMETABOLITES Indications ANTIBIOTICS Testicular cancer ALKYLATING Similar response to that of an orchiectomy AGENTS Advanced breast cancer MICROTUBULE Prostate cancer INHIBITORS AE’s: impotence, tumour flare (minimal compared to oestrogen Rx) STEROIDS HS AND ANTAGONISTS Leuprolide: 1. Sustained-release preparation, SC MONOCLONAL ANTIBODIES 2. Depot intramuscular injection Goserelin OTHERS IM administration Oestrogens ANTIMETABOLITES ANTIBIOTICS Examples: diethylstilbestrol & ethinyl estradiol Indications: ALKYLATING AGENTS Prostatic cancer MICROTUBULE Replaced by GnRH analogs INHIBITORS Mechanism of action STEROIDS HS AND ANTAGONISTS Inhibit the growth of prostatic tissue MONOCLONAL By blocking production of LH ANTIBODIES Decreasing synthesis of androgens in the testis OTHERS Oestrogens Adverse effects: Thromboemboli Myocardial infarction Hypercalcaemia Gynecomastia Impotence Monoclonal antibodies Directed at Rituximab specific targets Thus have fewer Tositumomab Bevacizumab adverse effects Trastuzumab Examples: Alemtuzumab Cetuximab Gemtuzumab ozagamicin Nomenclature of monoclonal antibodies Rituximab Tositumomab Bevacizumab Trastuzumab Alemtuzumab Cetuximab Gemtuzumab ozagamicin Trastuzumab ANTIMETABOLITES Overexpression of transmembrane human epidermal growth ANTIBIOTICS factor-receptor protein 2 (HER2) Intrinsic tyrosine kinase activity ALKYLATING AGENTS Mediate cell growth and division by phosphorylating signal proteins MICROTUBULE INHIBITORS Trastuzumab targets the extracellular domain of HER2 growth receptor STEROIDS HS AND ANTAGONISTS Inhibits the proliferation of cells that overexpress the HER2 protein MONOCLONAL ANTIBODIES Decreasing number of cells in S phase TKIs Generally administered with paclitaxel OTHERS Trastuzumab Mechanism of action Down-regulation of HER2? Decrease in angiogenesis? Pharmacokinetics IV Doesn’t cross BBB Adverse effects CHF: worsened in combination with anthracyclines Infusion-related: fever, chills, headache, dizziness, nausea, vomiting, abdominal pain, back pain Hypersensitivity reactions Rituximab ANTIMETABOLITES Monoclonal antibody against CD20 antigen on ANTIBIOTICS Normal and malignant B cells ALKYLATING AGENTS Plays a role in initiation of cell cycle and differentiation MICROTUBULE Indications: INHIBITORS Non-Hodgkin lymphoma STEROIDS HS AND ANTAGONISTS CLL MONOCLONAL Pharmacokinetics ANTIBODIES IV TKIs Causes rapid depletion of B cells OTHERS Rituximab ANTIMETABOLITES Mechanism of action ANTIBIOTICS Fab region of rituximab ALKYLATING AGENTS Binds to CD20 antigen on the B lymphocytes Fc region recruits immune effector functions MICROTUBULE INHIBITORS Complement Antibody-dependent, cell-mediated cytotoxicity of B cells STEROIDS HS AND ANTAGONISTS Commonly used in combination with: Cyclophosphamide MONOCLONAL ANTIBODIES Doxorubicin TKIs Vincristine Prednisone OTHERS Rituximab Adverse effects Hypotension, bronchospasm, angioedema First infusion: Chills & fever Release of TNFα & IL’s Pretreatment: diphenhydramine, acetaminophen, bronchodilators Cardiac arrhythmias Tumour lysis syndrome Acute renal failure, hyperkalaemia, hypocalcaemia, hyperuricaemia, hyperphosphatasaemia Leukopaenia, neutropaenia & thrombocytopaenia Less than 10% Tumour lysis syndrome Bevacizumab ANTIMETABOLITES ANTIBIOTICS Anti-angiogenesis agent Indication: ALKYLATING AGENTS metastatic colorectal cancer (combined with 5-FU) MICROTUBULE INHIBITORS IV administration, MOA: Attaches to & stops VEGF STEROIDS HS AND ANTAGONISTS From forming new blood vessels MONOCLONAL Thus tumours do not receive oxygen & essential ANTIBODIES nutrients TKIs Inhibiting tumour growth and proliferation OTHERS Bevacizumab ANTIMETABOLITES ANTIBIOTICS AEs: ALKYLATING AGENTS Common: hypertension, stomatitis & diarrhoea MICROTUBULE Less common: intestinal bleeding, proteinuria, INHIBITORS HF STEROIDS HS AND Rare: bowel perforation, opening of healed ANTAGONISTS wounds & stroke MONOCLONAL ANTIBODIES TKIs OTHERS Cetuximab Indication: Colorectal cancer (IV) Mechanism of action: Targeting the epidermal growth factor receptor On the surface of cancer cells Interfering with their growth Cetuximab Adverse effects Difficulty breathing Hypotension Pulmonary toxicity Other: rash, fever, constipation, abdominal pain Tyrosine Kinase Inhibitors ANTIMETABOLITES ANTIBIOTICS All have notable drug interactions due to interactions with: ALKYLATING AGENTS - CYP3A4 and or acid-reducing agents MICROTUBULE All are associated with cardiovascular INHIBITORS effects either due to: STEROIDS HS AND - Fluid retention OR Hypertension as SEs ANTAGONISTS MONOCLONAL ANTIBODIES TKIs OTHERS Imatinib Indications CML Gastrointestinal stromal tumour Mechanism of action Acts as a signal transduction inhibitor Inhibits tyrosine kinase activity Prevents subsequent phosphorylation Preventing cell proliferation Resistance Increased efflux/ Amplification of BCR/ABL gene Dasatinib & Nilotinib Adverse effects Fluid retention & oedema QT prolongation Hepatotoxicity Thrombocytopaenia & neutropaenia Nausea & vomiting Other tyrosine kinase ANTIMETABOLITES inhibitors ANTIBIOTICS ALKYLATING Erlotinib: AGENTS Inhibitor of epidermal growth factor receptor MICROTUBULE INHIBITORS kinase Indicated: STEROIDS HS AND ANTAGONISTS Non-small cell lung cancer MONOCLONAL ANTIBODIES Pancreatic cancer TKIs OTHERS Other tyrosine kinase ANTIMETABOLITES inhibitors ANTIBIOTICS Sunitinib: ALKYLATING AGENTS Inhibitor of serine/threonine and tyrosine kinases MICROTUBULE INHIBITORS Indicated: STEROIDS HS AND Renal cell carcinoma, GI stromal tumours, pancreatic ANTAGONISTS neuroendocrine tumours MONOCLONAL ANTIBODIES TKIs OTHERS OTHERS: Platinum coordination complexes Cisplatin indications: Solid tumours E.g. Metastatic testicular carcinoma In combination with: vinblastine & bleomycin Ovarian carcinoma In combination with: cyclophosphamide Bladder carcinoma: used alone OTHERS: Platinum coordination complexes Carboplatin Used when patients can’t be vigorously hydrated As needed with cisplatin In patients with renal failure or prone to neurotoxicity & ototoxicity Platinum coordination complexes ANTIMETABOLITES Mechanism of action ANTIBIOTICS Similar to the alkylating agents ALKYLATING AGENTS Loses its chloride ions intracellularly – active MICROTUBULE Binds to the guanine in DNA INHIBITORS Forms intra- and inter- strand cross links STEROIDS HS AND ANTAGONISTS Inhibiting DNA replication MONOCLONAL And RNA synthesis ANTIBODIES TKIs Cells are most vulnerable in G1 and S phases OTHERS  ANTIMETABOLITES Platinum coordination complexes ANTIBIOTICS Resistance ALKYLATING Elevated glutathione levels AGENTS Increased DNA repair MICROTUBULE Decreased cellular uptake INHIBITORS Pharmacokinetics STEROIDS HS AND IV, IA ANTAGONISTS Intraperitoneally Cisplatin: highly plasma protein MONOCLONAL ANTIBODIES bound TKIs Good distribution OTHERS  ANTIMETABOLITES Platinum coordination complexes: AE’s Severe persistent vomiting ANTIBIOTICS Pretreatment with antiemetics ALKYLATING Dose-limiting toxicity: nephrotoxicity AGENTS Problem with co-administration of aminoglycosides Extensive hydration MICROTUBULE INHIBITORS Hypomagnesaemia Hypocalcaemia STEROIDS HS AND Ototoxicity: hearing loss & tinnitis ANTAGONISTS Problem with aminoglyside administration Mild bone marrow suppression MONOCLONAL ANTIBODIES Neurotoxicity Carboplatin only causes mild nausea & vomiting TKIs It is not nephrotoxic, neurotoxic or ototoxic OTHERS Topoisomerase inhibitors: ANTIMETABOLITES Irinotecan & topotecan ANTIBIOTICS Topotecan indications: ALKYLATING AGENTS Resistant metastatic ovarian cancer Small-cell lung cancer MICROTUBULE INHIBITORS Colon or rectal cancer STEROIDS HS AND ANTAGONISTS In combination with 5-FU & leucovorin MONOCLONAL Mechanism of action ANTIBODIES TKIs S-phase specific Inhibit topoisomerase I OTHERS Topoisomerase inhibitors: ANTIMETABOLITES Irinotecan & topotecan ANTIBIOTICS ALKYLATING AGENTS Topoisomerases MICROTUBULE INHIBITORS Relieve torsional strain in DNA STEROIDS HS AND Topoisomerase inhibitors prevent re-annealing of ANTAGONISTS single strand breaks MONOCLONAL ANTIBODIES TKIs OTHERS Irinotecan & topotecan ANTIMETABOLITES ANTIBIOTICS Pharmacokinetics ALKYLATING IV administration AGENTS Renal dysfunction: dosage adjustment required MICROTUBULE INHIBITORS Resistance STEROIDS HS AND Increased efflux ANTAGONISTS Decreased ability to convert irinotecan to an active MONOCLONAL ANTIBODIES metabolite TKIs Down-regulation/mutation of topoisomerase I OTHERS Irinotecan & topotecan ANTIMETABOLITES ANTIBIOTICS Adverse effects: ALKYLATING Dose-limiting toxicity: myelosuppression & AGENTS neutropaenia MICROTUBULE Haematologic complications INHIBITORS Thrombocytopaenia & anaemia STEROIDS HS AND ANTAGONISTS Diarrhoea (atropine) , vomiting, alopaecia, headache MONOCLONAL ANTIBODIES TKIs OTHERS Etoposide ANTIMETABOLITES ANTIBIOTICS Mechanism of action: Block cells in S/G2 phase ALKYLATING AGENTS Topoisomerase II inhibitors Leads to double strand breaks MICROTUBULE INHIBITORS Indication Lung cancer STEROIDS HS AND ANTAGONISTS Testicular carcinoma In combination with bleomycin & cisplatin MONOCLONAL ANTIBODIES Resistance TKIs P-glycoprotein OTHERS Mutation of topoisomerase II Procarbazine ANTIMETABOLITES Undergoes a series of oxidative reactions to exert its ANTIBIOTICS cytotoxic action ALKYLATING on DNA, RNA & protein synthesis AGENTS AE’s: MICROTUBULE INHIBITORS Bone marrow suppression STEROIDS HS AND Nausea, vomiting, diarrhoea ANTAGONISTS Neurotoxic MONOCLONAL ANTIBODIES Monoamine oxidase inhibitor TKIs What should patients be warned against? Mutagenic & teratogenic OTHERS L-asparaginase ANTIMETABOLITES ANTIBIOTICS Tumour cells require extra asparagine Mechanism of action ALKYLATING AGENTS L-asparaginase hydrolyses asparagine MICROTUBULE INHIBITORS Catalyses the deamination of asparagine to aspartic acid & ammonia STEROIDS HS AND ANTAGONISTS Thus decreasing protein synthesis Indication MONOCLONAL ANTIBODIES ALL: in combination with vincristine & prednisone TKIs OTHERS L-asparaginase ANTIMETABOLITES Resistance ANTIBIOTICS Increased capacity of tumour cells to synthesize asparagine ALKYLATING AGENTS Pharmacokinetics IV: gastric enzymes destroy the drug MICROTUBULE INHIBITORS Adverse effects: STEROIDS HS AND Hypersensitivity reactions ANTAGONISTS Decrease in clotting factors MONOCLONAL ANTIBODIES Liver abnormalities TKIs Pancreatitis OTHERS Seizures & coma Interferons: α-2b ANTIMETABOLITES ANTIBIOTICS Mechanism of action Secreted by producing cells ALKYLATING AGENTS