Antitumor antibiotics and PLANT ALKALOIDS Antitumor antibiotics and PLANT ALKALOIDS Plant Alkaloids Vinca alkaloids : periwinkle plant (catharanthus rosea)

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  • Antitumor antibiotics and PLANT ALKALOIDS Antitumor antibiotics and PLANT ALKALOIDS Plant Alkaloids Vinca alkaloids : periwinkle plant (catharanthus rosea) Vincristine, Vinblastine and Vinorelbine Taxanes : Pacific Yew tree (taxus) Paclitaxel and Docetaxel Podophyllotoxins: Etoposide and Tenisopide Camptothecan analogs: Irinotecan and Topotecan. Antitumor Antibiotics By soil fungus Streptomyces. (multiple phases of the cell cycle ) Anthracyclines: Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, and Idarubicin. Chromomycins: Dactinomycin and Plicamycin. Miscellaneous: Mitomycin and Bleomycin.
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  • DNA G-segment A subunits ATP ATPase domain DNA T-segment A subunits tyrosine phenolic oxygens G-segment 5 DNA 3 OH group monomer tyrosine DNA tyrosine 4 base pairs transesterification DNA T-segment ATP ATP G-segment tyrosine 4 base pairs G-segment gate T-segment A subunits interface T-segment G-segment transesterification gate
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  • Antitumor Antibiotics Anthracyclines: Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, and Idarubicin. Chromomycins: Dactinomycin and Plicamycin. Miscellaneous: Mitomycin and Bleomycin.
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  • ANTHRACYCLINE
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  • Cardiotoxicity : is cumulative across members of the anthracycline (daunorubicin, doxorubicin, epirubicin, idarubicin) and anthracenedione (mitoxantrone) class of drugs. Acute (within 24 hrs, nonspecific ST-T wave change, sinus tachycardia, dysrhythmias, 40% ), Transient reduction in the ejection fraction can also occur acutely with pericarditis-myocarditis syndrome. Subacute (weeks to months after last dose, CHF with low cardiac output) Late effects (>5 yrs, incidence high 65% 4-10 yrs after receiving anthracyclines )
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  • Anthracyclines Risk factors Dose (< 450-550mg/m2, 1-10% CHF, 270 mg/m2 less cardiotoxicity ) 900 to 1000mg/m 2 CHF refractory to medical therapy. Cardiac irradiation or the administration of Cyclophosphamide may increase the risk of cardiotoxicity. Bolus Extreme young, advanced old Previous mediastinal radiation Malnutrition Pre-existing cardiac disease
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  • Anthracycline Mechanism of toxicity Dysrhythmias Sudden release catecholamines Cardiomyopathy damage to mitochondrial DNA of heart tissue free radical production
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  • Anthracyclines treatment Arrhythmia Monitor, no need treatment Cardiomyopathy Discontinuation of the drug and standard treatment of CHF. ACEI, carvedilol, drugs to decrease pre and after load. The cardioprotective agent dexrazoxane (Zinecard) recommended to be started at a doxorubicin cumulative dose greater than 350mg/m 2.
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  • Anthracyclines GI: Nausea/vomiting, mucositis Hematologic : leukopenia Radiation recall AML: 0.2% at 3 yrs. The tissue necrosis that occurs with extravasation may happen days to weeks after the treatment. Dose adjustment (ex: doxorubicin) liver function/bilirubin ALT/AST Bilirubin (mg/dl) Dose 2-3 x ULN - 75% > 3 x ULN or 1.2-3 50% - 3 - 5 25% - > 5 Do not administer
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  • Doxorubicin (Adriamycin) Stabilizing DNA-topoisomerase II complexes, DNA intercalation, and free radical formation. Absorption, Fate, and Excretion: T1/2= 30 hrs, metabolized in the liver. Adjust by liver dysfunction Preparation and Administration: IV bolus/ infusion, powerful vesicant. ADR Continuous infusion can decrease the risk of cardiotoxicity Therapeutic Indications in Hematology: Solid tumors, Hematologic malignancies : Hodgkin's disease (ABVD regimen), NHLs (CHOP, MACOP-B), and multiple myeloma (VBAP, VAD).
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  • Epirubicin CHF (0.9%, 1.6%, 3.3% at a cumulative dose of 550 mg/m(2), 700 mg/m(2), 900 mg/m(2) CHF increases rapidly with increasing total cumulative doses of epirubicin in excess of 900 mg/m(2) ADR Cardiac toxicity Secondary acute myelogenous leukemia (AML) MDS (0.27% at 3 years, 0.46% at 5 years and 0.55% at 8 years.
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  • Daunorubicin Biliary excretion accounts for approximately 75% of the drug and metabolite elimination. Patients with significant hepatic dysfunction should receive an attenuated dose of daunorubicin. Preparation and Administration: Red color to the urine for up to 72 hours after administration. Therapeutic Indications in Hematology: in combination with other drugs in the treatment of AML and ALL (45mg/m2/daily for 3 days)
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  • Idarubicin Acute lymphocytic leukemia Adult Acute myeloid leukemia induction, 12 mg/m(2) IV daily for 3 days in combination with cytarabine (dosed as 100 mg/m(2) every day by continuous infusion for 5-7 days every day. ADR less cardiac toxicity than doxorubicin or daunorubicin. There is no currently recommended maximum cumulative lifetime dose for idarubicin. Local erythematous streaking along the vein and facial flushing may result from too rapid administration. Radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of the idarubicin. Recurrent injury to a previously irradiated site may occur weeks to months following radiation.
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  • Mitoxantrone AML, ALL 12 mg/m2/day IV x 5 days for 1-2 cycles Maximum lifetime dose: 140 mg/m2 (no prior anthracycline, normal cardiac function, less in children) 120 mg/m2 (in combination with previous anthracycline, thoracic radiation or cyclophosphamide) 100 mg/m2 (previous maximum dose anthracyline, if cardiac assessment acceptable) Bone marrow transplant: much higher doses are used for tumour ablation prior to marrow transplant than for standard treatment regimens; eg, 12 mg/m2/day IV x 3 days or 60-75 mg/m2 IV in multiday, divided doses; in combination with other cytotoxic chemotherapy Dosage in myelosuppression: modify according to protocol by which patient is being treated. Dosage in hepatic failure: decrease dose by 50% if bilirubin >3mg/dl
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  • Mitoxantrone SPECIAL PRECAUTIONS: Cardiac monitoring is recommended prior anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin) or mediastinal radiotherapy and/or patients with pre-existing cardiac disease. Cardiac monitoring (echocardiogram, ejection fraction) is advisable every 2-3 cycles, and before every cycle in patients who have received a total cumulative dose of 140 mg/m2 (approximately 10 courses). The cumulative dose is lower in children and in patients who have received radiation to the mediastinal area or concomitant therapy with other cardiotoxic agents such as cyclophosphamide. Stomatitis is dose-limiting with the 5 day schedule and with the high doses used for bone marrow transplantation (eg, high grade mucositis in nearly 70% of BMT patients in one study). The majority of extravasations of mitoxantrone result in a blue discolouration of the skin which slowly fades.
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  • Dactinomycin Mechanism At low concentrations, dactinomycin inhibits DNA-primed RNA synthesis by intercalating with guanine residues of DNA. At higher concentrations, it also inhibits DNA synthesis. Interstrand and DNA- protein cross-links may also occur. (cell cycle phase-nonspecific) The tissue necrosis that occurs with extravasation may happen days to weeks after the treatment. Radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of the dactinomycin. Recurrent injury to a previously radiated site may occur weeks to months following radiation. Hepatotoxicity Wilm's tumour : increased AST (SGOT) and bilirubin levels, ascites and liver enlargement. (thrombocytopenia may accompany hepatotoxicity ). Factors: concurrent other hepatotoxic agents, especially halogenated anesthetics; using single-dose dactinomycin as opposed to a 5 day regimen; doses of dactinomycin 60 mcg/kg; and radiation. Adults: Direct intravenous: q2w: 1.25 mg/m2, q3-4w: 1-2 mg/m2 (25-50 mcg/kg) q4-6w: 400-600 mcg/m2/day (max :500mcg) x 5 days
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  • Bleomycin MECHANISM OF ACTION: Bleomycin causes DNA strand scission through formation of an intermediate metal complex requiring a metal ion cofactor such as copper or iron. This action results in inhibition of DNA synthesis, and to a lesser degree, in inhibition of RNA and protein synthesis. The drug is cell-cycle specific for G phase, M-phase and S phase Indication : Malignant pleural effusion, Soft tissue sarcoma, Testicular cancer. Use with caution in patients with compromised pulmonary function, with compromised renal function, > 40 years, receiving concomitant chest radiation, receiving concomitant administration of cisplatin, cyclophosphamide, methotrexate or doxorubicin, receiving positive fluid balance during prolonged surgical procedures and who smoke. These are all risk factors that can predispose the patient to bleomycin pulmonary toxicity (BPT), which can be severe and life threatening. A cumulative dose > 450 units known risk factor ( BPT).
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  • Bleomycin Dermatologic effects The most frequent adverse effects of bleomycin (50%) usually occurring 2-4 weeks after initiation of therapy. Adverse mucocutaneous effects including erythema, rash, striae, vesiculation, hyperpigmentation, and tenderness of skin usually develop in the second or third week of bleomycin therapy. Mucocutaneous effects appear to be dose related, usually occurring after 150-200 uni