Antimetabolites (Antineoplastics II) - Fitz Flashcards
What are the four antineoplastics that are natural products and consequently increase P-glycoprotein expression?
- Vincristine
- Paclitaxel
- Doxorubicin
- Etoposide
Long term use of what drug causes CHF?
Doxorubicin
What antineoplastic causes hemorrhagic cystitis?
Cyclophosphamide
What drug reverses hemorrhagic cystitis caused by an antineoplastic drug?
MESNA
What drug causes BOTH renal toxicity and ototoxicity?
Cisplatin
What two antineoplastics cause neurotoxicity?
Vincristine & Paclitaxel
What antineoplastic drug prevents DNA synthesis category, but is not actually an antimetabolite?
Hydroxyurea
Why is it important to monitor serum Methotrexate levels during the initial course of drug treatment?
High Methotrexate levels in the blood require additional Leucovorin rescue.
When a patient does not respond to antineoplastic drug therapy, what things should you be concerned about?
- Resistance
- Decreased activation
- Inherited deficiency of the metabolic enzyme (how drug is eliminated, increased toxicity if drug not eliminated)
What drug that we need to know causes Tumor Lysis Syndrome?
6-mercaptopurine
What are you going to do if a patient being treated with 6-mercaptopurine develops Tumor Lysis Syndrome?
Give Allopurinol! (excess uric acid)
Decrease dose of 6-MP (by 25%)
What are the two groups/mechanisms of drugs that prevent DNA synthesis?
- Nucleotide synthesis inhibitors
- blocking production of nucleotides
- Inhibitors of DNA synthesizing enzymes
- inhibit DNA polymerase
What are the three folic acid analogues that are nucleotide synthesis inhibitors?
- Methotrexate
- Pemetrexed
- Pralatrexate
What is the MOA of folic acid analogues? Differences in the three drugs?
competitive inhibitors of DHFR
- MTX blocks DHFR more, and Thymidylate Synthase less
- P drugs block DHFR less, and TS more
What are possible forms of resistance to folate analogues?
- Change target enzyme
- decrease DHFR affinity for MTX
- increase DHFR expression
- decrease polyglutamination
- decrease accumulation of drug by decreasing transport
- decrease expression of Reduced Folate Carrier
What is unique about the pharmacokinetics of folate analogues?
- Have to use transport systems that are used by a cell to bring folate in
- increased sensitivity in cells/tissues where folate receptor is increased
- increased resistance where Reduced Folate Carrier expression is reduced
How are folate analogues administered?
- MTX can be given orally for non-antineoplastic Tx
- Antineoplastic Tx: given IV or intrathecally to cross BBB
How much of folate analogue drug is excreted unchanged in urine? How does this affect patients with altered kidney function?
- Excreted 90% unchanged in urine
- decreased kidney function → severe bone marrow suppression
- administer with bicarbonate to maintain concentrations appropriately
- Drug interactions: NSAIDs, Cisplatin (nephrotoxic), weak acids (Aspirin)
- alter renal excretion
What are the therapeutic uses of folate analogues?
- MTX: extremely broad spectrum antineoplastic
- P drugs: more selective action
- mesothelioma, NSCLC
What are the potential cytotoxic side effects of folate analogues?
- primary toxic effects are on bone marrow
- pneumonitis (cough, fever and interstitial infiltrate)
- hepatic fibrosis
- alopecia, dermatitis
- MTX is abortifacaent
What is the advantage of Leucovorin Rescue?
- allows use of higher doses of MTX
- decreases toxicity
- shorten treatment term
- decrease chance of resistance
When is Leucovorin administration fatal?
When given intrathecally (CNS)
What are the two pyrimidine analogues?
- 5-Fluoruracil
- Capecitabine
What is MOA of pyrimidine analogues?
- 5-FU: inhibits thymidylate synthase
- Capecitabine: converted to 5-FU in cancer cells → inhibits thymidylate synthase
- Cells unable to make dTMP
Why is Leucovorin also used in antineoplastic treatment with pyrimidine analogue drugs?
increases binding of 5-FU to thymidylate synthase
(increases 5-FU efficacy)
What are two potential forms of resistance to pyrimidine analogues?
- changes in target enzymes
- increased expression of thymidylate synthase
- decreased activation of prodrugs
- decreased pyrimidine monophosphate kinase activity
What is event is important for 5-FU to function?
- activation of drug
- drug must enter pyrimidine synthesis pathway (3 steps)
- pyrimidine monophosphate kinase (form of resistance)
- drug must enter pyrimidine synthesis pathway (3 steps)
How are folate analogue antineoplastics eliminated?
- broken down by dihydropyrimidine dehydrogenase
- significant metabolic degradation occurs (~80% of the drug is eliminated by hepatic metabolism and 20% by renal excretion)
- many other tissues also degrade 5-FU (GI tract, so cannot give drug orally)
- inherited deficiency of dihydropyrimidine dehydrogenase leads to greatly increased drug sensitivity (~8% of US population)
What are the therapeutic uses of pyrimidine analogues?
- tends not to be particularly effective when given alone - synergistic with METHOTREXATE
- colorectal cancer (most widely used drug for this purpose)
- ovarian and breast cancer (part of CMF and FAC regimens)
What are the possible toxic side effects of pyrimidine analogues?
- 5-FU has a low therapeutic index (even for an antineoplastic drug)
- primary toxic effects are on bone marrow
- myelosuppression reaches maximum in 9-14 days
-
acute cerebellar syndrome (somnolence, ataxia of trunk or extremities, unsteady gait, slurred speech, nystagmus)
- occurs within weeks/months of initiating treatment in 5% of patients
- complete recovery following cessation of treatment
- alopecia, dermatitis
- hand-foot syndrome (palmar-plantar erythrodysesthesia)
What two drugs are purine analogues?
- 6-Mercaptopurine
- 6-Thioguanine
How do 6-MP and 6-TG become activated?
HGRPT in the Salvage Pathway of purine synthesis
What enzyme do purine analogues block?
Guanylyl kinase and cause “pseudofeedback inhibition”
(GMP builds up)
What does the inhibition of guanylyl kinase and “pseudofeedback inhibition” result in?
- interference with DNA and RNA synthesis
- inhibition of purine nucleotide interconversion
- a decrease in intracellular levels of guanine nucleotides (inhibition of glycoprotein synthesis)
- incorporation of purinethiols into both DNA and RNA, leading to DNA damage
What are potential forms of resistance to purine analogues?
- changes in target enzymes
- decreased ability to inhibit PNP and HGPRT
- decreased activation of prodrugs
- decreased expression of activation enzymes (esp. HGPRT)
- increased inactivation
- increased rates of degradation of the drugs or their “activated” analogues
What are possible toxic side effects of purine analogues?
- primary toxic effects are on bone marrow
- anorexia, nausea and vomiting occur in 25% of adults; less often in children
- as with any drugs used to treat leukemias, can cause TUMOUR LYSIS SYNDROME
How are purine analogues administered?
orally
What are the two metabolic pathways of 6-MP in the liver? What are “issues” of these systems?
- xanthine oxidase oxidizes 6-MP to 5-thiouric acid, which is inactive
- DOSE MUST BE ADJUSTED IF GIVEN WITH ALLOPURINOL (due to TUMOUR LYSIS SYNDROME)
- if you are treating the gout with Allopurinol, you must decrease 6-MP dose
- methylation and subsequent oxidation
- the enzyme responsible (thiopurine methyltransferase) has no known natural function, and polymorphic inheritance; 15% of the UK population has little or no enzyme activity, which causes increased toxicity
T/F Unlike 6-MP, 6-TG can be administered concurrently with ALLOPURINOL.
True
(different metabolism)
What are the therapeutic uses of purine analogues?
- acute leukemias
- 6-TG is synergistic with CYTARABINE
What are the four antineoplastic drugs that inhibit DNA synthesizing enzymes?
- PYRIMIDINES: CYTARABINE (Ara-C), GEMCITABINE (converted into compounds that compete with/mimic CDP and CTP)
- PURINE: CLADRIBINE, FLUDARABINE (converted into compounds that compete with/mimic ADP and ATP)
What is the MOA of DNA synthesizing enzyme inhibitors?
- incorporated into DNA where they block DNA polymerases (α = DNA synthesis and β = DNA repair)
- also inhibit ribonucleotide reductase
What DNA synthesizing enzyme inhibitor is not considered an Antimetabolite?
Hydroxyurea
What are three effects of Cytarabine (Ara-C)?
- blocks DNA elongation
- can cause repititions → mutagenic
- forces differentiation of cells
What cause cell apoptosis when treating with Gemcitabine?
DNA strand termination
What diseases/conditions is Hydroxyurea used to treat?
- CML
- sickle cell anemia
- increases production of fetal hemoglobin γ, interfering with the polymerization of HbS, and therefore decreasing painful crises in patients with severe sickle cell disease
What is unique about Hydroxyurea?
synchronizes cells in a radiation-sensitive phase of the cell cycle (G1)
