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 dihydrofolate reductase

Resistance to chemotherapy

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)

Given with chemotherapy protocol to

decrease toxicities

Protect healthy cells but not cancer

cells

Recombinant human erythropoetin (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 erythropoetin, epoetin alfa and epoetin beta, are available.

Epoetin alfa can 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

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

o Stimulates bone marrow to produce WBCs

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

• 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

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

The released serotonin may stimulate vagal afferents, thereby 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

• Lorazepam