1. Cytotoxic Drugs. III
Dr. Yieldez Bassiouni

2. MECHANISMS OF RESISTANCE TO CANCER CHEMOTHERAPY

3. 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).

4. 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).

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

6. 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’

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

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

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

10. Management of Toxic Side Effects of Cytotoxic Drugs

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

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

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

19. 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.