Cancer III Flashcards
What are cell cycle specific drugs?
Antimetabolites
What are cell cycle non-specific drugs?
Alkylating agents
How do antimetabolites work?
Inhibit DNA/RNA synthesis - S-phase specific
What does methotrexate do?
Antimetabolite that is structurally related to folic acid and so inhibits dihydrofolate reductase - targets cells in the S phase
What is methotrexate remained as in red blood cells?
MTX-polyglutamate compounds
How can the dose of methotrexate be reduced if it is too high?
Leucovorin
How are high doses of methotrexate delivered?
IV, IM and intrathecally
How does the unchanged drug appear?
In the urine
Does methotrexate have poor or good penetration into the CNS?
Poor
When is 6-mercaptopurine used?
Maintenance remission in acute lymphoblastic leukaemia and inhibits purine biosynthesis. Incorporated into DNA and RNA leading to non-functional molecules
How can resistance to 6-mercaptopurine arise?
Lack of HGPRT or increased drug metabolism
What does 6-fluorouracil do?
Deplete intracellular nucleotide pools - interferes with production of dTMP which is needed for DNA synthesis and cell growth
What is 6-fluorouracil often given with?
MTX
Can 6-fluorourcail cross the BBB?
Yes - excreted in the urine along with metabolites
What is gemcitabine an analogue of?
Deoxycytidine - metastatic pancreatic cancer
How is gemcitabine administered?
IV and deaminated to a non-toxic product
What is a major side effect of gemcitabine?
Myelosuppression
What is cytarabine an analogue of?
Cytosine arabinose or AraC that is incorporated into DNA and causes chain termination as no nucleotide can then be added onto it
What does dactinomycin do?
Intercalates into the major groove of DNA and interfere with transcription and DNA replication
What is dactinomycin used in combination with and why?
MTX as resistance is prevalent due to P-glycoprotein
What are the two anthracyclines?
Doxorubicin and daunorubicin
What do anthracyclines do?
Intercalate with DNA and generate free radicals that break DNA strands - can also interfere with the dan breakage repair system
What are anthracyclines used in combination for?
Lung, breast and leukaemia
Where do metabolites of anthracyclines appear?
Bile and urine - poor penetration into the CNS
What stage of the cell cycle do anthracyclines target?
S phase and G2 phase
What do alkylating agents do?
Transfer alkyl groups to DNA, are mutagens and target rapidly diving cells
What do some alkylating agents need for metabolic transformation?
P450
What can alkylating agents be used in combination to treat?
Solid and lymphatic tumours
Oral and can cross the BBB so can be used in brain cancer therapy
What are platinum coordinated complexes?
Cisplatin, carboplatin and oxaliplatin
Carboplatin is less toxic than cisplatin
What do platinum coordinated complexes do?
From intra and inter strand crosslinks and interferes with DNA replication and transcription and therefore it acts in G1 and S phase
What is oxiplatin used in?
Colorectal cancer
What are the two topoisomerase I inhibitors?
Topotecan and irinotecan - S phase specific
What can topotecan be used against?
Metastatic ovarian cancer and lung cancer
What can irinotecan be used against?
Colorectal and rectal cancer alongside 5_FU & leucovorin
What is the active form of irinotecan?
SN-38 - metabolised in cancer cells to form the active component
How do irinotecan and topotecan work?
Prevent ligation following topoisomerase cleavage
Bind to the enzyme-DNA duplex
How are topoisomerase I inhibitors administered?
Through IV and excreted in urine
What is a problem with topotecan?
Myelosuppression
What are topoisomerase II inhibitors?
Daunorubicin and doxorubicin - intercalate into DNA
Etoposide and teniposide - bind to transient cleavable form of enzyme-DNA complex leading to double strand breaks
What are telomerase inhibitors?
Imetelstat - direct enzyme inhibitors
Modify oligonucleotides
When do vinca alkaloids target cells?
Mitosis
What do taxanes do?
Block mitosis in metaphase by binding to tubulin and inhibiting its polymerisation and stability of microtubules
Induce spindle dysfunction
When are taxanes active?
G2/M phase
What are taxanes used to treat?
Ovarian cancer and breast cancers as well as non-small cell lung cancer
What are the two vinca alkaloids?
Vincristine and vinblastine
Are vinca alkaloids neurotoxic?
Yes
Where is telomerase active?
Stem cells
Where is telomerase inactive?
Somatic cells
What is Etoposide used in combination with for testicular cancer?
Bleomycin & cisplatin
What does teniposide treat?
Glinomas and neuroblastomas
Can alkylating agents be used in brain cancer?
Yes - they are oral bioavailable and cross the BBB
What does topoisomerase do?
Reversible single-stranded breaks in the DNA a duplex which act to relieve torsional strain
Where do platinum coordinated complexes metabolites go to?
The urine - poor penetration into the CNS
