PHAR420 Cancer Chemotherapy: Plant Derivatives PDF

1 2 3AY_AAG PHAR420 Cancer Chemotherapy: casticat a Plant derivatives the · Prof. Abdelali Agouni, MSc, PhD, FHEA source (they are...

1 2 3AY_AAG PHAR420 Cancer Chemotherapy: casticat a Plant derivatives the · Prof. Abdelali Agouni, MSc, PhD, FHEA source (they are etotoxics) Professor of Pharmacology plant deriva College of Pharmacy, Qatar University Office: F A2.01 Phone: +974 4403 5610 (extension #5610) 23AY_AAG 1  2 2 3AY_AAG Learning Outcomes By the end of lecture, the student will be able to: List the four main sub classes of plant alkaloids used as cancer chemotherapeutic agents. Identify the prototype drug under each sub-class. Classify the plant alkaloids based on their mechanism of action. Explain the mechanism of action & chemotherapeutic properties of microtubule targeting drugs. Explain the mechanism of action & chemotherapeutic properties of topoisomerase inhibitors. List the therapeutic indications and major adverse effects of plant alkaloids. 23AY_AAG 2  3 Plant Derivatives 2 3AY_AAG Vinca Taxanes Camptothecins Epipodop- alkaloids Paclitaxel Irinotecan hyllotoxin Vinblastine Docetaxel Topotecan Etoposide Vincristine Cabazitaxel Teniposide Vinorelbine Vindesine Microtubule Topoisomerase targeting drugs inhibitors 23AY_AAG 3  4 Microtubules 2 3AY_AAG Hollow cylindrical tubes that O polymerize from tubulin subunits. 8 Tubulins are structural proteins. g Tubulins are made from α & β subunits. O Microtubules must constantly add tubulin to maintain G will maintain stability. · B I a adde mychromosomes & Balance between it e If I accelerate prevent polymerization & ↑ I devision will cell e is the depolymerization is crucial for S ae cell division. chromosom the chromosomes If I want to bring If balance is disturbed, the cell => to polymarize to the middle I need. is unable to divide. - - If I want to bring the chromosomes the sides I need to depolymarize to 23AY_AAG 4  5 2 3AY_AAG Microtubule – Targeting Drugs Mechanism of Action: Mitosis M-phase cell cycle specific. O Mitotic inhibitors, or “spindle poisons.” O ↑ target will they Bind to the the spindles the end of tubiulin inside Bind tubulin the 23AY_AAG 5  6 2 3AY_AAG Microtubule – Targeting Drugs * VINCA ALKALOIDS * TAXANES Bind specifically to β-tubulin at the Bind to a different site on β-tubulin - bind end of microtubules. to the inside of microtubules. at the middle Inhibit the assembly of new Prevent microtubule disassembly into tubulin to the microtubule. tubulin monomers. Inhibit microtubule polymerization Stabilize polymerized microtubules. Arrest cell in mitosis and lead to Arrest cell in mitosis and lead to the the activation of apoptosis. activation of apoptosis. * Taxanes inhibit depolymerization 23AY_AAG Vinca alkaloids block polymerization 6 &  7 2 3AY_AAG 1. Vinca alkaloids Vinblastine & Vincristine are natural alkaloids ⑳ derived from the Madagascar Periwinkle plant (Vinca rosea). 8 Vinorelbine is a semi-synthetic Vinca alkaloid.. Vindesine is a synthetic derivative of Vinblastine. 23AY_AAG 7  & 8 2 3AY_AAG 1. Vinca alkaloids * Mechanism of Action: Inhibit microtubule polymerization. Arrest cells in mitosis and cause apoptosis. Formulation: IV only: Vincristine, Vinblastine & Vindesine ⑧ Vincristine must be labeled as - “Fatal if given intrathecally. For intravenous use only.” IV or Oral: Vinorelbine ⑨ 23AY_AAG 8  9 2 3AY_AAG 1. Vinca alkaloids Clinical Uses Vinblastine: For testicular carcinomas, Hodgkin's & non- Hodgkin’s lymphoma & Kaposi's Sarcoma. O VinCristine: For pediatric leukemia and pediatric tumors. children O Vinorelbine: ⑨ B For non–small cell lung cancer, breast D cancer and ovarian cancer. ⑨ Vindesine: For leukemia, lymphoma, melanoma, breast cancer and non-small cell lung cancer. 23AY_AAG 9  10 1. Vinca alkaloids 2 3AY_AAG Side effects and Toxicity: Neurotoxicity & myelosuppression. · Note : in combination Cause neurotoxicity in the following order of activity: don't O use therapy we 2 nurotoxic - 2 nephrotoxic together Vincristine > Vinorelbine > Vindesine> Vinblastine. - - the most neurotoxic least myelosupression myelosuppression more peripheral CNS > - neuropathy. Vincristine 8 & causes mild myelosuppression, severe neurotoxicity with peripheral neuropathy & paralytic ileus, results in severe constipation bone marrow suppression Vinblastine O b causes dose-limiting myelosuppression, mild neurotoxicity, GI distress, alopecia, and mucositis. Vinorelbine O and Vindesine cause intermediate myelosuppression and neurotoxicity. G ▫ Vinorelbine also causes constipation. be given orally 23AY_AAG 10  11 2 3AY_AAG 2. Taxanes Docetaxel: An alkaloid ester derived from the Pacific O yew (Taxus brevifolia) and the European yew (Taxus baccata). Paclitaxel O and Cabazitaxel – Semi-synthetic taxanes. &Mechanism of Action: Stabilize polymerized microtubules. Arrest cells in mitosis and lead to apoptosis. 23AY_AAG 11  12 2. Taxanes 2 3AY_AAG Formulation IV: Paclitaxel, Docetaxel, Cabazitaxel Clinical Use: nothing specific Paclitaxel: Ovarian cancer, Non-small cell lung cancer and Kaposi's sarcoma. Docetaxel: Breast, gastroesophageal, prostate and non–small cell lung cancer. Cabazitaxel: Advanced prostate cancer. IMP ! Side effects & Toxicity: Myelosuppression and neurotoxicity Paclitaxel: Myelosuppression, peripheral Op P sensory neuropathy, and possible hypersensitivity reactions during infusion. G Docetaxel: Neurotoxicity, fluid retention, myelosuppression with neutropenia. Cabazitaxel: Allergic reaction during infusion; neutropenia; less neurotoxicity. O ↳ we give a pre-treatment of Dexamethasone 23AY_AAG 12  13 2 3AY_AAG Topoisomerase inhibitors 23AY_AAG 13  14 Topoisomerase 2 3AY_AAG http://www.youtube.com/watch?v=EYGrElVyHnU Nuclear enzymes that cleave and unwind DNA to relieve torsional stress. Necessary for DNA replication and RNA transcription. They are 2 types: Topoisomerase I O - Cuts a single strand of one DNA double helix. Topoisomerase O II - Cuts both strands of one DNA double helix. 23AY_AAG 14  15 2 3AY_AAG Topoisomerase inhibitors Mechanism of action: S O phase cell cycle specific 23AY_AAG 15  16 Topoisomerase inhibitors 2 3AY_AAG * Camptothecins * Epipodophyllotoxin Topoisomerase I inhibitor Topoisomerase II inhibitor. Cuts made in single strand of one Cuts made in two strands of one DNA molecule. DNA molecule. Bind to transient DNA- Form a stable ternary complex with topoisomerase I cleavable complex Topoisomerase II and DNA. (reversible). Prevent rejoining of DNA strands. The collision of a DNA with this The collision of a DNA with this cleaved strand causes an cleaved strand causes an irreversible DNA break, leading to irreversible DNA break leading to apoptosis. - ↳ at the end we are over whelming apoptosis. the repare mechanism & cause apoptosis. Note: Although Epipodophyllotoxins bind to tubulin, they have no effect on microtubular structure or function at usual concentrations (due to reversible binding). 23AY_AAG 16  17 2 3AY_AAG 3. Camptothecins Topotecan & Irinotecan: Plant alkaloids derived from S a Chinese tree Camptotheca acuminata. · elective very # Mechanism of action: Topoisomerase I Inhibitors. Cause irreversible DNA breaks, leading to apoptosis. 23AY_AAG 17  18 3.Camptothecins 2 3AY_AAG & Topotecan: IV & PO Formulation Irinotecan: IV only formulation Clinical Use: Topotecan is used for advanced ovarian cancer, small cell lung cancer and cervical carcinoma. Irinotecan is used for metastatic colorectal cancer. ↳ used if the Patient can't tolarate oxaliplatin IMP ! * Side effects & Toxicity: Myelosuppression and GI irritation Topotecan also O causes dose-limiting mucositis and diarrhea. Irinotecan also causes severe diarrhea, ⑧ requiring treatment with IMP atropine and/or loperamide. 23AY_AAG 18  19 4. Epipodophyllotoxins 2 3AY_AAG Etoposide & Teniposide: Extracted from mandrake root O of the Mayapple tree Podophyllum peltatum Mechanism of Action: Topoisomerase II Inhibitors g Cause irreversible DNA breaks, O leading to apoptosis. 23AY_AAG 19  20 4. Epipodophyllotoxins 2 3AY_AAG Etoposide & Teniposide: IV formulation Clinical Use: Etoposide for testicular cancer and small cell lung cancer. Teniposide has limited utility and primarily given for acute leukemia in children. Toxicity: Dose-limiting myelosuppression, GI irritation and alopecia. # Etoposide also causes hypotension (the IV drug should be administered slowly). 23AY_AAG 20  21 2 3AY_AAG CHEMOTHERAPEUTIC DRUGS: PLANT DERIVATIVES CLASSIFICATION CLINICAL USE ADVERSE EFFECTS & MOA know which one is more neurotoxic 1. VINCA ALKALOIDS: Inhibit microtubule polymerization. · & which is more my elosuppression Mild myelosuppression, severe Pediatric leukemia & neurotoxicity with peripheral Vincristine Pediatric tumors neuropathy & paralytic ileus results in severe constipation Testicular carcinomas, Dose-limiting Hodgkin's & non-Hodgkin’s myelosuppression, mild Vinblastine lymphoma & Kaposi's neurotoxicity, GI distress, Sarcoma alopecia, mucositis. Leukemia, lymphoma, Intermediate myelosuppression Vindesine melanoma, breast cancer & & neurotoxicity non-small cell lung cancer For non–small cell lung Same as Vindesine but also Vinorelbine (Oral) cancer, breast cancer and causes constipation. & IV ovarian cancer 23AY_AAG 21  22 2 3AY_AAG CHEMOTHERAPEUTIC DRUGS: PLANT DERIVATIVES CLASSIFICATION CLINICAL USE ADVERSE EFFECTS & MOA 2. Taxanes: Stabilize polymerized microtubules. Myelosuppression, peripheral Ovarian cancer, Non- sensory neuropathy, and Paclitaxel small cell lung cancer possible hypersensitivity and Kaposi's sarcoma reactions during infusion. Breast, gastroesophageal, Neurotoxicity, fluid retention, Docetaxel prostate and non–small myelosuppression with cell lung cancer neutropenia. Advanced prostate Allergic reaction during Cabazitaxel cancer infusion; neutropenia. within the same # Each drug different class can target of types cancer. 23AY_AAG 22 &  23 2 3AY_AAG CHEMOTHERAPEUTIC DRUGS: PLANT DERIVATIVES CLASSIFICATION CLINICAL USE ADVERSE EFFECTS & MOA 3. Camptothecins: Topoisomerase I Inhibitors Advanced ovarian cancer, Myelosuppression, dose-limiting Topotecan (Oral) small cell lung cancer and mucositis and diarrhea cervical carcinoma Metastatic colorectal Myelosuppression and severe Irinotecan cancer diarrhea 4. Epipodophyllotoxins: Topoisomerase II Inhibitors Testicular cancer and Myelosuppression, GI irritation Etoposide small cell lung cancer and alopecia Same as Etoposide but also Teniposide Acute pediatric leukemia cause hypotension N.B: All plant derivatives are given IV. Vinorelbine and Topotecan are also given orally. 23AY_AAG 23  24 Learning Resources 2 3AY_AAG Chapter 38: Pharmacology of Cancer: Genome Synthesis, Stability, and Maintenance. David A. Barbie, David A. Frank, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 3e. (LWW Health Library) Chapter 61: Cytotoxic Agents, Chabner, Bruce A., et al. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14e. (Access Pharmacy) Chapter 54. Cancer Chemotherapy. Katzung & Trevor’s Pharmacology: Examination & Board Review, 10e. (Access Pharmacy) Chapter 54: Cancer Chemotherapy. Katzung BG, Masters SB, Trevor AJ. Katzung B.G., Masters S.B., Trevor A.J. eds. Basic & Clinical Pharmacology, 16e. (Access Pharmacy) Chapter 104: Cancer Treatment and Chemotherapy, Shord SS, Medina PJ. Shord S.S., Medina P.J. In: Pharmacotherapy: A Pathophysiologic Approach, 9e. (Access Pharmacy) 23AY_AAG 24