MECHANISMS OF RESISTANCE TO CANCER 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)

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

Resistance to chemotherapy

Given with chemotherapy protocol to

decrease toxicities

Protect healthy cells but not cancer

cells

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

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

o The CSFs are so-called because they stimulate the formation of maturing colonies of leucocytes in vitro

o Stimulate bone marrow to produce WBCs

o They reduce the severity / duration of neutropenia induced by cytotoxic drugs

• 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

• 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

Cytotoxic drugs triggers release of serotonin from enterochromaffin cells in the gastrointestinal tract

Serotonin stimulates nerve receptors and vagal afferents, initiating the vomiting reflex

• Very High – Cisplatin– Nitrogen Mustard

• High – Methotrexate

• Moderate – Carboplatin

• Low – Bleomycin– 5-FU

• Very Low – Vinca Alkaloids

• 5HT3 blockers– 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.