L27-28 Drugs used in the the treatment of maliganant diseases I and II→ Flashcards
Chemotherapy: classification based on the
mechanism of action
Cytotoxic drugs, which include:
→Plant derivatives (vinca alkaloids, taxanes, campothecins) - most of these
specifically affect microtubule function and hence the formation of the
mitotic spindle.
→Alkylating agents, acting by forming covalent bonds with DNA and thus
impeding replication;
→Antimetabolites, drugs that interfere with the formation of key biomolecules including nucleotides, the building blocks of DNA
→Antitumor antibiotics, i.e. substances of microbial origin that prevent
mammalian cell division
→Hormones, of which the most important are steroids, namely glucocorticoids,
oestrogens and androgens, as well as drugs that suppress hormone
secretion or antagonize hormone action.
→Miscellaneous agents that do not fit into the above categories. This group
includes a number of recently developed drugs designed to affect specific
tumor-related targets.
Name, MoA and Side effect of Vinca alkaloids
vincristine and vinblastine
Useful in the treatment of metastatic testicular carcinoma, lymphomas, advanced non–small cell lung cancer
Mechanism of action: →They bind to tubulin →→Prevent polymerization to form microtubules →→→Dysfunctional spindle in metaphase, prevent chromosomal segregation and cell proliferation.
Metabolized by cytochrome P450 in liver
– Doses must be modified in patients with impaired hepatic function
Adverse effects
→phlebitis or cellulitis, nausea, vomiting, diarrhea, and alopecia.
Name, MoA and Side effect of Taxanes
Paclitaxel and Docetaxel
Good activity against advanced
ovarian cancer, metastatic breast cancer, non-small cell lung cancer.
Mechanism of action: →bind reversibly to the tubulin subunit →promote polymerization of tubulin and stabilization. →→ microtubule cannot dissolve →→ Inhibit microtubule disaggregation →→→ prevent cell division
Hepatic metabolism by the cytochrome P450 system, biliary excretion
Adverse effect:
→neutropenia
→Docetaxel is contraindicated in patients with cardiac disease
→Patients to be treated with paclitaxel are
premedicated with dexamethasone,
diphenhydramine and H1+H2 blocker due to serious hypersensitivity reactions.
Name, MoA and Side effect of Topoisomerase inhibitors
Supercoiling occurs during DNA replication, which prevent DNA replication to proceed → Topoisomerase enzymes unwind and wind DNA to facilitate DNA replication to continue
→ Topoisomerase I induces single-
strand break in DNA
→ topoisomerase II induces double-
strand break in DNA
→→Topoisomerase inhibitors prevent topoisomerase from religating DNA strands after cleavage. This leaves the cell with DNA breaks, which cause cell death
Topoisomerase-I Inhibitors
e.g.topotecan and Irinotecan
→topotecan employed in metastatic ovarian cancer when primary therapy has failed and also in the treatment of
small-cell lung cancer. Irinotecan is used as a first-line drug for the treatment of colon or rectal carcinoma.
Topotecan and irinotecan are infused IV. Both the drugs and their active metabolites are eliminated in urine.
→Therefore, the dose may have to be modified in patients with impaired
kidney function.
Adverse effects of topotecan and irinotecan
→Bone marrow suppression, particularly neutropenia.
Topoisomerase-II Inhibitors
etoposide (VP-16) and teniposide (VM-26)
→Etoposide:lung carcinoma and testicular carcinoma.
→Teniposide: second-line agent in the treatment of acute lymphocytic leukemia
Etoposide may be administered either IV or orally, whereas teniposide is only administered IV. They are metabolized and converted to glucuronide and sulfate conjugates and are excreted in urine.
→ Drugs that induce the CYP450 system lead to an acceleration of
teniposide metabolism.
Adverse effects of etoposide and teniposide
→Myelosuppression (primarily leukopenia)
Name, MoA and Side effect of Alkylating Agents
cyclophosphamide, ifosfamide,
Mechanism of action:
→The alkylating agents exert their toxic
effects by covalently binding to
nucleophilic groups on various cell
constituents.
→The alkyl group is attached to the
guanine base of DNA.
→ Alkylation of nucleotides lead to
abnormal base pairing, DNA breakage
(scission) and cross-linking.
→They are mutagenic and carcinogenic,
and can lead to second malignancy.
Adverse effects of Cyclophosphamide and
Ifosfamide:
prominent toxicities are bone marrow depression and hemorrhagic cystitis, which can lead to fibrosis of the bladder.
Cisplatin
→Clinically used to treat almost every
solid tumor and lymphoma
Adverse effects
→severe nausea and
vomiting; major toxicity is dose-related
nephrotoxicity
Name, MoA and Side effect of Anti-metabolites
Methotrexate (MTX)
→Effective against acute
lymphocytic leukemia, breast cancer, and head and neck carcinomas.
→Mechanism of action: – Antifolates act by blocking the active site of dihydrofolate reductase (DHFR), an enzyme that reduces folic acid to its active reduced form (i.e. tetrahydrofolate). Tetrahydrofolate are co-enzymes necessary for methylation in various metabolic processes, which are important for the synthesis of nucleotides and amino acids.
Adverse effects
→Renal damage
→Hepatic function: long-term use leads to
cirrhosis
→Neurologic toxicities: intrathecal
administration
→Contraindications: avoid in pregnancy
Name, MoA and Side effect of Antitumor antibiotics
used in combination with other agents for
treatment of sarcomas and a variety of carcinomas, including breast and lung, as well as for treatment of acute lymphocytic leukemia and lymphomas.
Doxorubicin
Mechanism of action: →Intercalating between base pairs of DNA/RNA →Inhibiting topoisomerase II enzyme → Interacting with molecular oxygen, producing superoxide ions and hydrogen peroxide, which cause single-strand breaks in DNA
Adverse effect (most serious) →Irreversible, dose-dependent cardiotoxicity →→due to the generation of free radicals and lipid peroxidation.
An iron-chelator dexrazoxane helps to protect against the cardiotoxicity of doxorubicin.
Name, MoA and Side effect of Hormone Antagonists
Tamoxifen
Antiestrogens are first-line therapy for
treating estrogen receptor-positive
breast cancer.
Mechanisms of action
→They act by binding to the estrogen
receptors in the target cells, making the
estrogen unavailable to the tumor.
→ Tamoxifen is not a pure antiestrogen, but a selective estrogen receptor modulator (SERM) that has weak estrogenic activity producing estrogenic effects at various sites.
Adverse effects
Long-term effects of tamoxifen include endometrial cancer, strokes, and cataract formation.
Name, MoA and Side effect of Antibodies
Trastuzumab
HER-2/neu (also called erbB-2) is the gene that encodes for the human epidermal growth factor receptor type 2 • The HER-2/neu gene is amplified in up to 30% of human breast cancers
MoA →Trastuzumab specifically targets the extracellular domain of the HER-2 growth receptor, and inhibits the proliferation of cells that overexpress the HER2 protein
usually administered with paclitaxel,
can cause regression of breast cancer and
metastases.
Adverse effect (most serious) congestive heart failure.
Bevacizumab (Avastin®)
MoA
→attaches to and stops
vascular endothelial growth factor from stimulating the formation of new blood vessels.
→Without new blood vessels, tumors do not receive the oxygen and essential nutrients necessary for growth and
proliferation.
→ It is approved for use as a first-line drug against metastatic colorectal cancer
Adverse effects
→ hypertension, stomatitis, and
diarrhoea.
Problems associated with chemotherapy
Resistance (inherited and acquired resistance)
→ Due to an amplified gene that codes for a transmembrane protein, P-glycoprotein
→ Minimize by short-term and intensive therapy with combinations of drugs
Treatment-induced tumors
→May arise 10 or more years after the original cancer was cured. Especially a problem after therapy with cytotoxic drugs such as alkylating agents
