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What are the antimetabolites?
- DNA synthesis inhibitors
- Inhibit the actions of enzymes that are involved in the synthesis of DNA precursors and bases
what are the categories of antimetabolites?
- Folate analogues (aka Antifolates)
- Pyrimidine analogues
- Purine analogues
what are the folate analogues drugs?
what are the Pyrimidine analogue drugs?
- 5-Fluorouracil (5FU) (Adrucil)
- #1 tx for colorectal CA
- Results in a deficiency of dTMP (deoxythymidine diphosphate)
- Raltitrexed (Tomudex) ·
- Pemetrexed (Alimta)- non small cell lung CA·
- Cytarabine (Cytosar)·
- Gemcitabine (Gemzar)- pancreatic CA·
- Capecitabine (Xeloda)
what are the Purine analogs?
- Mercaptopurine (6- MP), (Purinethol)
- Fludarabine (Fludara) (Oforta)
- Pentostatin (Nipent)
- Cladribine (Litak) (Movectro)·
- Thioguanine (Tabloid)
- Methotrexate (Novantrone)
- Competitively inhibits DHFR
- 5-Fluorouracil (5FU) (Adrucil)·
- Results in a deficiency of dTMP (deoxythymidine diphosphate)
- Mercaptopurine ·
- is metabolized to 6-thio-GTP·
- is incorporated into RNA and DNA, halting further DNA and RNA synthesis
- 6-thio-GTP can be incorporated into DNA and RNA, but because it is not a normal base, it halts further DNA and RNA synthesis.
- It is called a fraudulent nucleoside. – kills the cell
Acute Myeloid Leukemia Tx regime:
- cannot cross BBB, must inject it right into the brain – on exam ·
- Administrated orally, intravenously, intramuscularly, or intrathecally·
- CNS entry must be achieved via intrathecal administration
- Does not cross the blood-brain barrier
- Only a small fraction metabolized
- Majority eliminated unchanged in the urine
- Consider dose adjustments with renal impairment
kinetics of mercaptopurine:
- Available in oral dosage forms
- Metabolized by the liver
- Xanthine oxidase
- One of the enzymes responsible for mercaptopurine metabolism ( goes up)
- Inhibitors of this enzyme can lead to toxicity
- Ex. Allopurinol (allopurinol inhibits xanthine oxidase)
Non-small cell lung CA tx:1st line
- 1st line: Pemetrexed/ CISplatin, & hydration
- Premedications: Vitamin B12, Folic acid, dexamethasone
Indications for methotrexate:
- Rheumatoid arthritis
- Acute lymphoblastic leukemia
- Severe psoriasis·
- Non-Hodgkin's lymphoma
- Cancers of the breast, brain, head, and neck, ovary, bladder
indications for Pemetrexed?
- Non-small cell lung cancer (non-squamous)
indication for Thioguanine, Mercaptopurine
- Thioguanine (AML), Mercaptopurine (ALL)
indications for Fludarabine, Cladribine (HCL), Pentostatin, Cytarabine
- Brain (cytarabine only)
indications for 5-FU?
- Cancers of the breast, colon and rectum, stomach, head and neck, skin (noninvasive)
- Actinic keratoses (thick, scaly, or crusty patches of skin)
indications for Gemcitabine:
Cancers of the pancreas, lung (non-small cell cancer), ovary, bladder, esophagus, head and neck
Colon CA tx- 1st line:
what can you substitute the 1st line for?
- OXALIplatin, Leucovorin, Fluorouracil. mFOLFOX6
- Can substitute capcitabine, bc it is a metabolite of 5-FU
- 5 FU is gold standard
SE for folate analogues:
- Damage to GI epithelium
- Dermatitis ·
- Defective oogenesis or spermatogenesis
- Acute: reversible elevations in liver enzymes
- Chronic: cirrhosis
SE of purine analogues:
- Develops gradually
- Most severe with Thioguanine
- Nausea and vomiting
- With Chronic mercaptopurine use
- Altered mental status and seizures
Pyrimidine analogues (5-FU) SE:
- Particularly cytarabine ·
- GI effects (severe diarrhea) and stomatitis –on exam
- Palmar-plantar erythrodysesthesia( PPE)
- Aka “Hand-foot Syndrome” (24-40%)
- Drugs that causeHand-foot Syndrome :
- Xeloda® (capecitabine )
- Cytosar-U® (cytarabine)·
- FUDR® (floxuridine)·
- 5-FU (fluorouracil)·
- Idamycin® (idarubicin)
- Doxil® (liposomal doxorubicin)
- Sutent® (Sunitinib)
- Nexavar® (Sorafenib)
- Continuous infusion of (Adriamycin®) doxorubicin·
- Reversible hepatotoxicity ·
- When intrathecal administration or high plasma levels
- Cerebellar (ataxia)
- Cerebral (seizures, dementia, coma)
chemo induced diarrhea drugs:
Fluorouracil, capecitabine, methotrexate, cytarabine
folate analogue (methotrexate) DI:
- Tubular secretion plays a role in the excretion of methotrexate
- Agents that compete for secretion at the proximal tubule may reduce methotrexate clearance
CI for folate analogue (methotrexate)?
every person on 5-FU gets what drug?
what is it? & what does it do?
- Leucovorin (Folinic acid)- This increases effectiveness to kill ca
- Reduced form of folic acid·
- Decreases side effects of methotrexate (antifolate) (use with pentotrexate)
- Cirrhosis, pneumonitis
- It is metabolized to mTHF·
- This increases the cytotoxic effects of 5-FU by increasing and stabilizing the binding of FdUMP to thymidylate synthetase
Pharmacogenetics of Thiopurine methyltransferase (TPMT):
- Plays a role in the metabolic inactivation of mercaptopurine·
- Approximately 15% of Caucasians have reduced activity of this enzyme
- Greater risk for toxicity
What is Dihydropyrimidine dehydrogenase (DPD)? on exam
- One of the enzymes involved in the metabolic inactivation of 5-fluorouracil·
- Korean patients tend to have higher DPD activity·
- African Americans tend to have lower activity
- Increased 5-FU toxicity
what is the mech of resistance for antimetabolites?
- Reduced transport across cell membranes
- Changes in the conformation of the DHFR enzyme
- Increased concentrations of DHFR
- Increased drug efflux
what is description of Bleomycin?
- Belongs to a family of glycopeptides
- Exert a cytotoxic effect by damaging DNA
- In the Anti-tumor Antibiotic class
Bleomycin (Blenoxane®) – has low myleosuppression
- Is an intercalator which inserts itself into the DNA structure which produces single and double stranded breaks
- Skin and lung lack hydrolase which results in increased toxicities
- So SE on skin and lung
- Bleomycin binds with FE(III)-OOH
Indication for Bleomycin?
- Lymphoma; “owl eyes”
- Cancers of the head and neck, cervix, testicles, bladder
CI for Bleomycin?
what makes Bleomycin a good candidate for use in multi-drug regimes?
- causes minimal bone marrow suppression
- (unlike most cytotoxic agents)
SE of Bleomycin?
- Due to the lack of hydrolase activity
- Nausea, vomiting
Serious SE of Bleomycin?
- Interstitial pneumonitis or fibrosis: -on exam
- Very serious complication
- Fatal outcome in 1% of patients
- Risk increases: Higher doses, Advanced age(>70 years), Preexisting pulmonary disease
- Hypersensitivity reaction
mech of resistance of Bleomycin?
- Increased hydrolase activity
- Leads to increased inactivation of bleomycin
- Decreased uptake of bleomycin into cancer cells
- Repair of DNA strand breaks
- Inactivation of bleomycin