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Cytotoxic Drugs - III

Cytotoxic Drugs - III. By Dr . Yieldez Bassiouni.

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Cytotoxic Drugs - III

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  1. Cytotoxic Drugs - III By Dr. YieldezBassiouni

  2. 1-  cell repair mechanisms: e.g.  DNA repair causing resistance to alkylating agents 2-  inactivation of the drug by enzymes (purine & pyrimidine antimetabolites)3 - production of trapping agents (e.g. glutathione which conjugate with alkylating agents)4- Resistance to methotrexate due to  level and  affinity to dihydrofolatereductase Resistance to chemotherapy

  3. P–glycoprotein • P–gp or multidrug resistance protein 1 (MDR1) • It protects cells against environmental toxins like a 'vacuum cleaner', picking up foreign chemicals, such as drugs, as they enter the cell membrane and expelling them. •  entry and accumulation of drugs(e.g. doxorubicin, vinblastine)

  4. Chemoprotectants “ Rescue Therapy “ • Given with chemotherapy protocol to decrease toxicities • Protect healthy cells but not cancer cells

  5. Leucovorin • A form of tetrafolate that is accumulated more readily by normal than tumor cells, and this results in rescue of the normal cells as leucovorin (folinic acid) bypass the blocked DFR • A large doses of ‘Methotrexate’ can be given • To overcome drug resistance to MTX

  6. MESNA Mercaptoethanesulfonate traps acrolein released from cyclophosphamide and thus reduces the incidence of “ hemorrhagic cystitis “

  7. Dexrazoxane Inhibits free radicle formation and protects against the cardiac toxicity- induced by anthracyclines‘Doxorubicin’

  8. Allopurinol It is commonly administered before initiating chemotherapy of leukemias and solid tumors to prevent hyperuricemia

  9. Management of Toxic Side Effects of Cytotoxic Drugs

  10. Cancer-Related Anemias • Recombinant human erythropoetin (epoetin) • Erythropoietin is produced in juxtatubular cells in the kidneyand in macrophages • Its stimulates erythroid cells to proliferate and generate erythrocytes

  11. Cancer-Related Anemias • Two forms of recombinant human erythropoetin, epoetinalfa and epoetin beta, are available. • Epoetinalfacan be given IV or SC to treat anemia due to chronic renal failure and cancer chemotherapy • Can reduce transfusion requirement in cancer patients • Darbopoetin, a is a synthetic form of erythropoietin, has a longer half-life and can be administered less frequently

  12. Colony Stimulating Factors • The CSFs are so-called because they stimulate the formation of maturing colonies of leucocytes in vitro • Stimulates bone marrow to produce WBCs • They reduce the severity / duration of neutropenia induced by cytotoxic drugs “Paclitaxel”

  13. Granulocyte CSF • G-CSF stimulates neutrophil production • Recombinant forms “filgrastim” are used therapeutically • They reduce the severity / duration of neutropenia induced by cytotoxic drugs • Given either SC or by IV infusion

  14. Nausea & Vomiting Cytotoxic drugs triggers release of serotonin from enterochromaffin cells in the gastrointestinal tract The released serotonin may stimulate vagalafferents, thereby initiating the vomiting reflex

  15. Emetogenic Potential of Chemotherapy Drugs • Very High • Cisplatin • Nitrogen Mustard • High • Methotrexate • Moderate • Carboplatin • Low • Bleomycin • 5-FU • Very Low • Vinca Alkaloids

  16. Anti-emetics • 5HT3 blockers • Ondansetron • Granisetron • D antagonists • Metaclopramide • Phenothiazides • Chlorpromazine • Corticosteroids • Dexamethasone • Butyrophenones • Halopridol • Cannabinoids • Nabilone • Lorazepam

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