Cancer Chemo Agents- Nitrosoureas Flashcards
Name three nitrosoureas:
1) Carmustine
2) Lomustine
3) Semustine
Nitrosoureas are useful in treating what and why?
CNS tumors, they are lipid soluble and cross the BBB
What is Streptozotocin?
A glucosamine nitrosourea that is diabetagenic
Streptozocin is useful for treating…
islet cell carcinomas
How is streptozocin transported into the cell?
via Glut-2 transporter
What is expressed in high levels in the Glut-2 transporter?
B-ilset cells
Other alkylating agents:
1) procarbazine
2) dacarbazine
3) altretamine
4) cisplatin
5) carboplatin
6) oxaliplatin
Procarbazine is what?
an oral agent used in combo agents for treating hodkin’s, non hodkins lymphomas and brain tumors.
Procarbazine has what properties?
leukemogenic, mutagenic, and teratogenic
Procarbazine prolongs what?
Prolongs interphase and causes DNA strand scission
When metabolized by CYP450, procarbazine produces what?
azoprocarbazine and H2O2- which causes strand scission
One of the metabolites from procarbazine is a…
MAO inhibitor thus cannot be combined with other MAO inhibitors
Dacarbazine undergoes
oxidative N-demethylation to monomethyl derivative, which decomposes to produce DIAZOMETHANE
What does diazomethane produce?
a methyl carbonium ion that is cytotoxic
Alretamine is indicated for…
oral form, approved for use in ovarian cancers unresponsive to other agents
What does Cisplatin cause?
intra-and inter-stand cross-linking by binding to N7 position of G and disrupts DNA metabolism
Cisplatin can cause what?
Nephrotoxicity- hence IV hydration is necessary to reduce nephrotoxicity
Carboplatinum is a…
2nd generation platinum analog
Carboplatinum has significantly less what compared to cisplatin?
less renal and Gi toxicity, and IV hydration is not necessary
Oxaliplatin is a what?
3rd generation diamno-cyclohexane platinum analog
Oxaliplatin treats what?
Advanced stage III colorectal cancer
Oxaliplatin is used in combo with?
5FU and leukovorin
Name Antimetabolites:
1) Methotrexate
2) Pemetrexed
3) Purine Antagonists- (6-thio, 6-mercapto, 6-thioguanine, Fludarabine, Cladribine)
4) Pyrimidine antagonists (5-florouracil, capecitabine, cytarabine, gencitabine)
Methotrexate MOA:
Folate analog that binds to active catalytic site of DHFR to inhibit the reduction of DHF into THF. THF is needed for the biosynthesis of Thymidylate, purine nucleotides, and serine and methionine.
What is necessary for the formation of intracellular cytotoxic MTX polyglutamates?
Folylpolyglutamate synthetase
Methotrexate resistance is due to:
1) decreased drug transport
2) decreased formation of MTXpolyglutamates
3) Increased expression of DHFR by gene amplification (double minutes and HSR)
4) Altered DHFR with reduced affinity for MTX
5) mulit-drug resistant P170 glycoprotein transporter may cause resistance
Pemetrexed MOA:
is a pyrrolpyrimidien antifolate analog activated by FPGS, inhibits DHFR and thymidylate synthase.
Purine Antagonists:
1) Thiopurines- purine analogs
6-mercaptopurine MOA:
requires phophoribosylation by HGPRT (hypozanthine, guanine phosphoribosyl transferase) by the salvage pathway into the active form that inhib’s several enzymes
What med will not work in HGPRT deficient individuals?
6-mercapto
Metabolites from 6-mercapto that contribute to cytotoxic action?
Thiogualylic acid and 6-methylmercaptopurine
6-mercapto indication:
used in the treatment of childhood leukemia
6-MC is converted to thiouric acid by…
xanthine oxidase
What is frequently given with cancer chemo agents to prevent hyperuricemia?
Allopurinol
Allopurinol inhibits what?
xanthine oxidase
What drug gets metab’d into mercaptopurine?
Azathiopurine
6-thioguanine MOA:
inhibits several enzymes in the de novo purine nucleotide biosynth pathway and nucleotide interconversion. Upon ribo-phospho-ribosylation, will incorporated into DNA and RNA
Resistance to 6TG is due to?
1) decrease expression of HGPRT
2) increased expression of alkaline phosphotase that causes dephosphorylation of thiopurine nucleotides
3) increase expression of thiopurine methyl transferase (TMPT)
Fludarabine MOA:
rapidly dephosphorylated to 2 flouro-arabinofuranosyladenosie and phosphorylated to triphosphate by cell doxycytidine kinase.
The triphosphate of Fludarabine inhibits?
DNA pol-a and DNA pol-B- inhibiting DNA syth and repair
The diphosphate of Fludarabine inhibits?
ribonucleotide reductase
Cladribine triphosphate inhibits
DNA pol-a and DNA pol-B-inhibiting DNA synth and repair
5-fluorouracil MOA?
irreversibly inhibits… synthase forming a ternary complex with reduced N5,10 methylenetetra hydrofolate; thus inhibiting thymidylate synthesis causing thymine less death.
5-FUTP interferes with…
RNA metabolism
5-dFUTP (5-deoxyribosyl nucleotides) inteferes with…
DNA metabolism
5-FU admin’d
IV
5-FU has what kind of bioavailability?
Poor oral bioavailability due to metabolism by dihydropyrimidine dehdryogenase in the gut mucosa
Clinical indication for 5-FU?
Colorectal carcinoma
Capecitabine is a…
fluoropyrimidine carbamate prodrug
Capecitabine oral bioavail?
70-80%
Capecitabine MOA:
Converted to 5’deoxy-5-fluorodeoxyuridine by cytidine deaminase. The nucleoside is then hydrolyzed to 5-FU by thymidine phosphorylase in the solid tumor.
Clinical indications for Capecitabine?
metastaic breast cancer, monotherapy for metastatic colorectal cancer
Cytarabine MOA:
converted to araCMP by deoxycytidine kinase, which is then converted to araCTP, which comp. inhibits DNA pol-a and B, which gets incorp’d into DNA and RNA to disrupt respective metabolisms.
araCTP competitively inhibits
DNA pol-a and DNA-pol-B
Why is Cytarabine highly dose dependent?
because it has S phase specificity
Gemcitabine’s diphosphate inhibits
ribonucleotide reductase
After gemcytabine, only what can be added resulting in chain termination?
only one gemcitabine nucleotide
