Cytotoxic Drugs. III Dr. Yieldez Bassiouni

MECHANISMS OF RESISTANCE TO CANCER CHEMOTHERAPY

Resistance to chemotherapy 1-  cell repair mechanisms: e.g.  DNA repair causing resistance to alkylating agents 2-  drug efflux by P–glycoprotein transporters “vacuum cleaner” to protect cells against environmental toxins  entry and accumulation of drug (e.g. doxorubicin, vinblastine) المقاومة Decreased accumulation of cytotoxic drugs in cells as a result of the increased expression of cell surface, transport proteins. These are responsible for multidrug resistance to many structurally dissimilar anticancer drugs (e.g. doxorubicin, vinblastine and dactinomycin; see Gottesman et al., 2002). An important member of this group is P-glycoprotein (PGP/MDR1). The physiological role of P-glycoprotein is thought to be the protection of cells against environmental toxins. It functions as a hydrophobic 'vacuum cleaner', picking up foreign chemicals, such as drugs, as they enter the cell membrane and expelling them. Non-cytotoxic agents that reverse multidrug resistance are being investigated as potential adjuvants to treatment. A decrease in the amount of drug taken up by the cell (e.g. in the case of methotrexate). Insufficient activation of the drug (e.g. mercaptopurine, fluorouracil and cytarabine). Some drugs require metabolic activation to manifest their antitumour activity. If this fails, they may be unable to block the metabolic pathways required to exert their effects. For example, fluorouracil may not be converted to FDUMP, cytarabine may not undergo phosphorylation, and mercaptopurine may not be converted into a fraudulent nucleotide. Increase in inactivation (e.g. cytarabine and mercaptopurine). Increased concentration of target enzyme (methotrexate). Decreased requirement for substrate (crisantaspase). Increased utilisation of alternative metabolic pathways (antimetabolites). Rapid repair of drug-induced lesions (alkylating agents). Altered activity of target, for example modified topoisomerase II (doxorubicin). Mutations in various genes, giving rise to resistant target molecules. For example, the p53 gene and overexpression of the Bcl-2 gene family (several cytotoxic drugs).

Resistance to chemotherapy 3 -  inactivation of the drug by enzymes (purine & pyrimidine antimetabolites) 4 - production of trapping agents (e.g. glutathione which conjugate with alkylating agents) 5- Resistance to methotrexate due to  level and  affinity to dihydrofolate reductase محاصرةtrapping agents Decreased accumulation of cytotoxic drugs in cells as a result of the increased expression of cell surface, energy-dependent drug transport proteins. These are responsible for multidrug resistance to many structurally dissimilar anticancer drugs (e.g. doxorubicin, vinblastine and dactinomycin; see Gottesman et al., 2002). An important member of this group is P-glycoprotein (PGP/MDR1). The physiological role of P-glycoprotein is thought to be the protection of cells against environmental toxins. It functions as a hydrophobic 'vacuum cleaner', picking up foreign chemicals, such as drugs, as they enter the cell membrane and expelling them. Non-cytotoxic agents that reverse multidrug resistance are being investigated as potential adjuvants to treatment. A decrease in the amount of drug taken up by the cell (e.g. in the case of methotrexate). Insufficient activation of the drug (e.g. mercaptopurine, fluorouracil and cytarabine). Some drugs require metabolic activation to manifest their antitumour activity. If this fails, they may be unable to block the metabolic pathways required to exert their effects. For example, fluorouracil may not be converted to FDUMP, cytarabine may not undergo phosphorylation, and mercaptopurine may not be converted into a fraudulent nucleotide. Increase in inactivation (e.g. cytarabine and mercaptopurine). Increased concentration of target enzyme (methotrexate). Decreased requirement for substrate (crisantaspase). Increased utilisation of alternative metabolic pathways (antimetabolites). Rapid repair of drug-induced lesions (alkylating agents). Altered activity of target, for example modified topoisomerase II (doxorubicin). Mutations in various genes, giving rise to resistant target molecules. For example, the p53 gene and overexpression of the Bcl-2 gene family (several cytotoxic drugs).

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

Leucovorin A form of tetrafolate (folinic acid)that is accumulated more readily by normal than tumor cells, and this results in rescue of the normal cells as leucovorin bypass the blocked DFR ‘MTX’

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

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

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

Management of Toxic Side Effects of Cytotoxic Drugs

Cancer-Related Anemias Recombinant human erythropoietin (epoetin) Erythropoietin is produced in juxtatubular cells in the kidney and in macrophages Its stimulates erythroid cells to proliferate and generate erythrocytes

Cancer-Related Anemias Two forms of recombinant human erythropoietin, epoetin alfa and epoetin beta, are available. Epoetin alfa can be given IV or SC to treat anemia during cancer chemotherapy Can reduce transfusion requirement in cancer patients Darbopoietin, a hyperglycosylated form of epoetin, has a longer half-life and can be administered less frequently

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

Granulocyte CSF G-CSF is 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

Granulocyte-Macrophages CSF GM-CSF is a hematopoietic growth factor that regulates production of granuloctyes (basophils, eosinophils, neutrophils) and other myeloid cells Sargramostim used to accelerate recovery of neutrophils after cancer chemotherapy

Nausea & Vomiting Cytotoxic drugs triggers release of serotonin from enterochromaffin cells in the gastrointestinal tract Serotonin stimulates nerve receptors and vagal afferents, initiating the vomiting reflex

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

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

Bisphosphonates drugs that are used to help strengthen and reduce the risk of fractures in bones that have been weakened by metastatic breast cancer. Example: zoledronic acid. Zoledronic acid may help other systemic therapies, like hormone treatment and chemo work better. Tumors in women getting zoledronic acid with chemo shrank more than those in the women treated with chemo alone.