Cancer Chemotherapy- DNA Synthesis Inhibitors Flashcards
(44 cards)
Why are Chemo agents given in combination (3)
- Produce synergistic activity
- Prevent drug resistance
- Decrease toxicity
What are the 2 Combination Chemotherapies used for Lung Cancer
- CAV
- C = Cyclophosphamide
- A = Adriamycin (doxorubicin)
- V = Vincrisitine
- CAE
- C = Cyclophosphamide
- A = Adriamycin
- E = Etoposide
What are the 2 Combination Chemotherapies used for Breast Cancer
- CMF
- C = Cyclophosphamide
- M = Methotrexate
- F = 5-Fluorouracil (5-FU)
- AC
- A = Adriamycin
- C = Cyclophosphamide
What are the 2 Combination Chemotherapies used for Colon Cancer
- FolFOx
- Fol = Folinic Acid (Leucovorin)
- F = 5-FU
- OX = Oxaliplatin
- FOLFIRI
- Fol = Folinic Acid (Leucovorin)
- F = 5-FU
- Iri = Irinotecan
What are the 2 Combination Chemotherapies used for Leukemias
Anakin Becomes Darth Vader, then CHOPS off Luke’s hand
- ABDV
- A = Adriamycin
- B = Bleomycin
- V = Vinblastine
- D = Darcarbazine
- CHOP-R
- C = Cyclophosphamide
- H = Hydroxydaunorubicin (doxorubicin)
- O = Oncovin (ie Vincristine)
- P = Prednisone
- R = Rituximab
For which Leukemias would you use the ABVD treatment combo
Hodgkins Lymphoma
For which Leukemias would you use the CHOP-R treatment combo
Non-Hodgkins Lymphoma
CLL
What are 4 classes of DNA Synthesis Inhibitors and examples of each
- Folate Antagonists: (Methotrexate)
- Purine Antagonists: (6-mercaptopurine , 6-thioguanine)
- Pyrimidine Antagonists: (5-Fluorouracil)
- Ribonucleotide Reductase Inhibitors: (Gemcitabine)
What is the Mechanism by which Methotrexate works and how does it show selective toxicity?
- DHFR converts folic acid to FH2(DHF) and FH4(THF)
- The THF is required for DNA and RNA synthesis (donates carbon group for purine synthesis)
- MTX binds to and inhibits DHFR to block synthesis of FH4 thus blocking DNA and RNA synthesis
-MTX is more selective for the Eukaryote DHFR than prokaryote DHFR (trimethoprim selective for pro dhfr) and accumulates in rapidly dividing cells since they require high levels of folate and nucleotide precursors
How is MTX taken into the cell and how is it processed once in the cell
- MTX enters the cell through the folate receptor or reduced folate transporter
- once inside it is polyglutamated by: Folypolyglutamate synthase
What is the significance of glutamated MTX
- Polyglutamated MTX is more active than MTX
- MTX inhibits DHFR
- Polyglutamated MTX also binds and inhibits TS (thymidylate synthase) which creates dTMP from dUMP and is needed to create dTTP and form DNA
How is Methotrexate:
- Administered
- Absorbed/Distributed (CNS?)
- Eliminated
- Oral or Parenteral
- Well absorbed and distributed
- No CNS penetration; intrathecal admin for ALL
- Renal Excretion
In which combination therapy and for which Cancer is Methotrexate used and what are its 2 non cancer uses
- CMF (cyclophosphamide, MTX, 5-FU)
- For Breast Cancer
NON Cancer Uses
- Rheumatoid arthritis
- Psoriasis
What are 5 adverse effects seen with Methotrexate and which is the primary one?
- Bone Marrow Suppression (primary dose limiting tox)
- GI toxicity
- Stomatitis
- Kidney damage
- Hepatotoxicity
What treatment is used to try to prevent adverse effects of Methotrexate and how does it work?
- Leucovorin (folinic acid) “Leucovorin Rescue”
- Can PREVENT but not reverse adverse effects
- Can donate a carbon group without being reduced by DHFR; this allows low level of DNA synthesis. The low level is enough to sustain and rescue normal cells but not the tumor cells who have a higher demand
What are the 3 mechanisms of resistance against Methotrexate
- Decreased Drug activation (Folypolyglutamate synthase down regulation)
- Increased target expression: more DHFR then can be inhibited
- Decreased drug accumulation: mutation and decreased expression of the two transporters (folate receptor and reduced folate transporter)
What is the class and mechanism of action of 6-mercaptopurine and 6-thioguanine
- Purine antagonists
- 6-MP and 6-TG are converted to Thio-dGTP by HPRT
- Thio-dGTP is incorporated into the growing DNA chain and inhibits the DNA polymerase terminating the chain
-MeTIMP (methyl thioinosine monophosphate) a metabolite of 6-MP also inhibits de novo purine biosynthesis
How is 6-Mercaptopurine:
- Administered
- Absorbed/Distributed (CNS?)
- Metabolized
- Eliminated
- Oral
- Absorption: Decreased by Food
- Well Distributed
- Does not cross BBB
- Inactivated by Thiopurine methyl transferase (TPMT) AND Xanthine Oxidase (XO)
- Renal Excretion
How is 6-Thioguanine:
- Administered
- Absorbed/Distributed (CNS?)
- Metabolized
- Eliminated
- Oral
- Absorption: Decreased by Food
- Well Distributed
- Does not cross BBB
- Inactivated ONLY BY TPMT (whereas 6-MP inactivated by TPMT AND XO)
- Renal Excretion
What are the Non-Cancer uses of 6-MP and 6-TG
- IBD (inflammatory bowel disease)
- Immunosuppressant
2 adverse effects of 6-MP and 6-TG and which is dose limiting and what can alter the toxicities
- Bone marrow suppression (dose limiting)
- Hepatotoxicity
Both can be affected by the TMPT levels of the patient in which some patients are deficient/have low activity
In what scenarios does the differing metabolisms of the purine antagonists come into play and which antagonist would then be favored?
- Variant type TMPT gene causing dec gene activity and dec drug inactivation: 6-MP would be favored due to additional degradation pathway by XO
- Those patients with gout on Allopurinol; it inhibits the XO enzyme and thus would cause accumulation and inc toxicity of 6-MP: thus 6-TG would be favored or 6-MP dose reduced
What is the Pathophysiology behind the Varient TMPT type effect on purine antagonists
- 25% of the population has an altered TMPT gene which decreases its activity (v/wt)
- and a smaller percentage have even less function (v/v type) they have severe hematopoieteic and hepatic toxicity requiring 90% dose reduction
What are 2 mechanisms of resistance to Purine antagonists
- Decreased Drug Activation: Low HPRT dec activation
- Inc Drug inactivation: High TPMT inc inactivation
