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- S phase Folate antagonists
- •Diarrhea, nausea, vomiting, and stomatitis
- •Myocardial infarction, angina, dysrhythmias, cardiac arrest, cardiac failure and ECG changes
- •Myelosuppression: Lymphopenia in 94% of patients
- •Hand-foot syndrome (45%): pain, redness, scaling or shedding of the skin of the palms and soles.
- •Fatigue, anorexia, paraesthsia, & headache
- •Myelosuppression: nadir 7-14 days, recovery usually rapid
- •Skin: Alopecia, maculopapular rash of extremities
- •CNS: somnolence and cerebellar ataxia occurs with about 1% incidence.
- •Ocular: conjunctivitis, lacrimation, blepharitis, and photophobia.
- Side effects:
- •Conjuctivitis/corneal toxicity: Prevent with steroid eye drops
- •High dose: cerebellar toxicity--ataxia
- •Mechanism of Action:
- –S phase dependent
- –Enzyme that inhibits ribonucleotide reductase which is necessary for DNA synthesis
- •Clinical Use: leukemia, myelodysplasia
- •Side effects
- –Skin: rash, hyperpigmentation, pruritus
- –Radiation recall
Vinca Plant Alkaloids
- M Phase inhibitor
- •Plant-based chemicals block cell division by inhibiting microtubule assembly (spindle fibers, made of microtubules, help separate the chromatids during cell division)
- •Examples: Vincristine, Vinorelbine, Vinblastine
- •Side effects: neuropathy, vesicant
- M Phase Inhibitor
- •Plant- based compounds
- •Increase stability of microtubules: prevents the separation of chromatids during mitotic anaphase
- •Examples: paclitaxel, docetaxel
- •Side effects: myelosuppression, neuropathy, fluid retention
- •FDA approved in January 2005
- •Albumin facilitates the administration of water-insoluble compounds
- •Allows delivery of a 49% higher dose of paclitaxel
- •Side effects: neuropathy
- •Semisynthetic analogue of epothilone B
- –Binds to beta-tubulin
- –Arrests tumor cells in the G2-M phase of the cell cycle triggering tumor cell apoptosis
- •Low susceptibility to tumor resistance mechanisms (ie efflux pumps)
- •Toxicity: neurologic
- G1 Phase inhibitor
- •Mechanism: hydrolyzes circulating L-asparagine to aspartic acid and ammonia resulting in inhibition of protein synthesis
- •Clinical use: ALL
- •Resistence: MDR
- •Side effect:
- –Hypersensitivity reaction
- –Decreases clotting factors (IX, Xi, protein C and S, antithrombin III, and fibrinogen)
- –Neurologic toxicity
- –Fever, chills, nausea, vomiting
- G2 Phase Inhibitors
- Topoisomerase: enzyme essential to maintain the topology of the DNA.
- •Resistance: altered target enzyme
- •Inhibition prevents the normal function of DNA: transcription, replication and repair.
- •Type I: camptothecins—irinotecan (GI) and topotecan (ovarian)
- •Type II: anthracyclines (breast, leukemia) and epipodophylotoxins (naturally appearing) etoposide (testicular).
- •Side effects: primarily GI--diarrhea
- G2 Phase inhibitor
- •Mechanism – Topoisomerase II inhibitor
- •Examples: Doxorubicin, Daunorubicin, Epirubicin, Idarubicin, Mitoxantrone
- •Side effects
- •Acute: arrhythmias, pericarditis, myocarditis
- •Chronic: CHF, dilated cardiomyopathy
- –Red-orange urine discoloration
- –Radiation recall skin reaction
- –Mitoxantrone: bluish discoloration of sclera, urine, and finger nails; Less cardiotoxicity and N/V than doxorubicin
- •Liposomal formulation evades detection and destruction by the immune system
- –increases the time the drug is in the body
- – majority of the drug stays inside the liposome while in the blood (at least 90%).
- •Side effects
- –Hand-Foot Syndome (HFS)
- – Mouth sores
- •Plant-derived compounds are primarily extracted from Podophyllum peltatum (American mayapple).
- •Prevent cancer cells from entering the G1 phase and affect DNA synthesis.
- •Examples: etoposide and teniposide
- •Side effects: secondary acute myelogenous leukemia (< 5 years)