Spindle Poisons

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Spindle Poisons

  1. 1. SPINDLE POISONS Tulasi Raman Moderator: Dr. Padmavathi S.
  2. 2. Mitotic Spindle
  3. 3. The Cell Cycle G1 S G2 M G0
  4. 4. Vinca Alkaloids Taxanes Estramustine Epothilones Colchicine Benzimidazoles Griseofulvin
  5. 5. VINCA ALKALOIDS 1. Vinblastine 2. Vincristine 3. Vinorelbine 4. Vindesine
  6. 6. Source • Madagascar periwinkle plant – Catharanthus roseus – Vinca rosea • Hypoglycemic effects in diabetes.
  7. 7. Mechanism of action • Cell-cycle–specific • Cell division arrests in metaphase. • Bind specifically to β-tubulin and to block its polymerization with α-tubulin into microtubules. • In absence of an intact mitotic spindle, duplicated chromosomes cannot align along the division plate. They disperse throughout the cytoplasm or may clump in unusual groupings • Apoptosis
  8. 8. Drug Resistance • Antitumor effects are blocked by multidrug resistance mediated by the mdr gene and its glycoprotein – Ca2+ channel blockers such as verapamil can reverse resistance of this type in vitro • MRP and the closely related breast cancer resistance protein, may mediate multidrug resistance • Mutations in β-tubulin or in the relative expression of isoforms of β-tubulin
  9. 9. Pharmacokinetics • Metabolised by liver cytochromes – Hepatic dysfunction (bilirubin >3 mg/dL), a 50- 75% reduction in dose • Excreted in bile • < 15% excreted unchanged in urine
  10. 10. Vinblastine • Given intravenously • Single dose of 0.3 mg/kg of body weight – Myelosuppression reaches its maximum in 7-10 days. If a moderate level of leukopenia (~3000 cells/mm3) is not attained, the weekly dose may be increased gradually by increments of 0.05 mg/kg of body weight. • Doses should be reduced by 50% for patients with plasma bilirubin >1.5 mg/dL.
  11. 11. • Clinical Applications – Metastatic testicular tumor • Vinblastine, Bleomycin and Cisplatin – Hodgkins disease • ABVD - Adriamycin, Bleomycin, Vinblastine and Dacarbazine
  12. 12. Toxicity – Leukopenia • Occurs within 7-10 days, after which recovery ensues within 7 days – Mild neurological manifestations – GI disturbances • Nausea, Vomiting , Diarrhoea, Anorexia – Syndrome of inappropriate secretion of antidiuretic hormone – Extravasation during injection may lead to cellulitis and phlebitis
  13. 13. Vincristine • Given Intravenously • 2 mg/m2 of body surface area at weekly or longer intervals • Doses should be reduced by 50% or 75% for patients with plasma bilirubin >1.5 mg/dL or >3 mg/dL
  14. 14. • Clinical Applications – With glucocorticoids is the treatment of choice to induce remissions in childhood leukemia – In combination with alkylating agents and anthracycline for pediatric sarcomas
  15. 15. Toxicity – Neurological symptoms • Motor dysfunction – Severe constipation • Colicky abdominal pain and obstruction – May be prevented by a prophylactic program of laxatives and bulk-forming agents – Alopecia • Reversible, frequently without cessation of therapy – Modest Leukopenia • Thrombocytopenia – Anemia – GI cholic and Obstipation – Syndrome of inappropriate secretion of antidiuretic hormone • Inadvertent injection into the CSF causes a devastating and often fatal irreversible coma and seizures
  16. 16. Vinorelbine • In normal saline as an intravenous infusion over 6-10 minutes • Doses of 30 mg/m2 either weekly or for 2 out of every 3 weeks.
  17. 17. • Clinical Applications – With cisplatin for the treatment of non–small cell lung cancer – Oral formulation is active in non–small cell lung carcinoma
  18. 18. Toxicity – Granulocytopenia – Modest cytopenia – Less neurotoxicity – Allergic reactions – Mild reversible changes in liver enzymes • Doses should be reduced by 50% or 75% in patients with plasma bilirubin 2.1-3 mg/dL or >3 mg/dL
  19. 19. TAXANES 1. Paclitaxel 2. Docetaxel
  20. 20. Mechanism of Action • It binds specifically to the B-tubulin subunit of microtubules and antagonizes the disassembly of this key cytoskeletal protein • Cell killing is dependent on both drug concentration and duration of cell exposure • Cell death occurs by apoptosis
  21. 21. Drug Resistance • Increased expression of the mdr-1 gene and its product, P-glycoprotein • B-tubulin mutations • Increase in survivin, an anti-apoptotic factor • Increase in aurora kinase, an enzyme that promotes completion of mitosis • Upregulating the BIII-isoform of tubulin
  22. 22. Drug interactions • The sequence of cisplatin preceding paclitaxel decreases paclitaxel clearance and produces greater toxicity • Paclitaxel decreases doxorubicin clearance and enhances cardiotoxicity
  23. 23. Paclitaxel • Source – Bark of the Western yew tree – Semisynthesis from 10-desacetylbaccatin
  24. 24. • Cremaphor – 50% ethanol and 50% polyethoxylated castor oil • Responsible for a high rate of hypersensitivity reactions • Pretreatment with a histamine H1-receptor antagonist such as diphenhydramine, an H2-receptor antagonist such as cimetidine and a glucocorticoid such as dexamethasone • Albumin bound Nanoparticle – Soluble in aqueous solutions – Increased peripheral neuropathy – Not be given to patients with decreased absolute neutrophil count
  25. 25. Pharmacokinetics – 3 hour infusion every 3 weeks – 1 hour infusion weekly – Metabolised by hepatic cytochromes • 6-OH paclitaxel, inactive – < 10% excreted in urine unchanged – Clearance is non-linear • Decreases with increased dose – Presence of hepatic metastases >2 cm in diameter decreased clearance and led to high drug concentrations in plasma and greater myelosuppression.
  26. 26. Toxicity – Neutropenia – Stock & Glove sensory neuropathy – Myalgias – Mucositis – Hypersensitivity reactions – Asymptomatic bradycardia – Silent ventricular tachycardia
  27. 27. Docetaxel • Semi-synthetic • Administered in polysorbate 80 • Pharmacokinetics – Linear – Heaptic cytochromes • Inactive metabolites
  28. 28. Toxicity – Increased neutropenia – Fluid retention • Peripheral edema • Pleural fluid • Peritoneal fluid • Pulmonary edema • Progressive interstitial pneumonitis • Respiratory failure – Oral dexamethasone ameliorates fluid retention
  29. 29. Uses • Metastatic ovarian cancer • Breast cancer • Lung cancer • GI cancer • Genitourinary cancer • Head and neck cancer
  30. 30. Estramustine • Combination of estradiol coupled to normustine through a carbamate link • Mechanism of action – Binds to B tubulin and microtubule-associated proteins, causing microtubule disassembly
  31. 31. Pharmacokinetics – Orally – Extensive first pass metabolism – Oxidised 17 keto derivative • Active – Excreted in faeces • Inactive metabolites – Inhibits clearance of taxanes
  32. 32. Uses – Prostatic Cancer • Metastatic • Locally advanced hormone refractory
  33. 33. Toxicity – Myelosuppression – Estrogenic side effects • Gynecomastia • Impotence • Elevated risk of thrombosis • Fluid retention – Hypercalcemia – Acute attacks of porphyria – Impaired glucose tolerance – Hypersensitivity reactions • angioedema.
  34. 34. Epothilones • Sorangium cellulosum – Myxobacterium • Isolated from soil on the bank of the Zambezi River in southern Africa • Mechanism of Action – Bind to B-tubulin – Microtubule stabilisation – Cell-cycle arrest at the G2-M interface – Apoptosis
  35. 35. Resistance – Less susceptible to P-glycoprotein-mediated multidrug resistance – Mutation of the B-tubulin binding site – Upregulation of isoforms of B-tubulin
  36. 36. Pharmacokinetics – Ixabepilone • Intravenously – Less solubile • Polyoxyethylated castor oil / ethanol – Hepatic cytochrome clearance • Dose – 40 mg/m2 over 3 hours every 3 weeks
  37. 37. Uses – Metastatic Breast Clearance • Monotheraphy • Combination therapy – Anthracyclines – contraindicated in patients with a baseline neutrophil count <100,000 – cells/mm3, serum transaminases >2.5 x ULN or bilirubin above normal
  38. 38. Toxicity – Neutropenia – Peripheral sensory neuropathy – Fatigue – Diarrhea – Asthenia
  39. 39. BENZIMIDAZOLES • Thiabendazole • Mebendazole • Albendazole
  40. 40. Mechanism of action • Inhibits of microtubule polymerization by binding to β-tubulin • Higher affinity for parasite β -tubulin • Inhibition of mitochondrial fumarate reductase • Reduced glucose transport • Uncoupling of oxidative phosphorylation
  41. 41. Pharmacokinetics • Thiabendazole is soluble in water • Mebendazole and albendazole are poorly soluble • Low systemic bioavailability – poor absorption and – Rapid first-pass hepatic metabolism • 95% bound to plasma proteins • Active metabolite - Mebendazole • Excreted in Bile as Inactive metabolites
  42. 42. • Albendazole absorption is enhanced by the • presence of fatty foods and possibly by bile salts. • Rapidly metabolized in the liver to albendazole sulfoxide, which has potent anthelmintic activity • 70% bound to plasma proteins • Excreted mainly in the urine
  43. 43. Uses • Thiabendazole – Cutaneous larva migrans (creeping eruption) – Strongyloidiasis • Mebendazole – Enterobiasis, a single 100-mg tablet – Ascariasis, Trichuriasis, or Hookworm infections, 100mg BD for 3 days
  44. 44. • Albendazole • Enterobiasis, ascariasis, trichuriasis, and hookworm), single oral 400-mg dose by adults • and children >2 years of age. • In children between the ages of 12 and 24 months, the WHO recommends a reduced dose of 200 mg.
  45. 45. • Drug of choice for treating cystic hydatid disease due to Echinococcus granulosus – 400mg BD for 1-6 months • Only drug available with useful activity against alveolar echinococcosis caused by E. multilocularis • Parasiti-static rather than -cidal, and lifelong therapy with or without surgical intervention
  46. 46. • Preferred treatment of neurocysticercosis caused by larval forms of Taenia solium • recommended dosage is 400 mg given twice a day for adults for 8-30 days • Glucocorticoid therapy is usually begun before initiating albendazole therapy to reduce the incidence of side effects resulting from inflammatory reactions to dead and dying cysticerci.
  47. 47. GRISEOFULVIN • Inhibits microtubule function – Disrupts assembly of the mitotic spindle • Binding sites on the microtubular protein are distinct • In addition, interacts with microtubule- associated protein
  48. 48. Pharmacokinetics • Improved absorption when the drug is taken with a fatty meal. • Micro-sized and ultra-micro-sized powders • Primary metabolite is 6-methylgriseofulvin. • Griseofulvin is deposited in keratin; the drug is tightly bound to, and persists in, keratin, providing prolonged resistance to fungal invasion.
  49. 49. Uses • Tinea capitis • Tinea cruris • Tinea corporis • Tinea of the hands & beard • Tinea pedis • Topical Therapy is sufficient in most cases
  50. 50. COLCHICINE • Rx of Gout • Inhibits tubular formation – Anti-mitotic effects – Release of histamine-containing granules from mast cells – Secretion of insulin from pancreatic cells – Movement of melanin granules in melanophores
  51. 51. • May alter neutrophil motility • Decreases the crystal-induced secretion of chemotactic factors and superoxide anions by activated neutrophils. • Limits neutrophil adhesion to endothelium by modulating the expression of endothelial adhesion molecules.
  52. 52. Pharmacokinetics • Oral absorption is rapid but variable • 50% of colchicine is protein bound • Significant enterohepatic circulation • Dose must be decreased for patients with impaired renal function. • 10-20% is excreted in the urine
  53. 53. • Acute Gout – Two doses taken 1 hour apart: 1.2 mg (two tablets) at the first sign of a gout flare followed by 0.6 mg (one tablet) 1 hour later. • Dose for prophylaxis is – 0.6 mg taken orally 3 or 4 days/wk for patients who have <1 attack per year – 0.6 mg daily for patients who have >1 attack per year – 0.6 mg two or three times daily for patients who have severe attacks.
  54. 54. THANK YOU !

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