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37 Cards in this Set
- Front
- Back
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Chemotx problems...
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-slow growing tumor may not respond as well
-poorly vascularized tumor may not receive suff conc of drug -drug resistance by tumor |
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When is chemotx used?
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-when surgery/radiotx fails to completely remove tumor, cells eventually metastasize
-reduce the chance of metastasis - used as adjunct tx when surgery and radiotx are 1st options |
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Alkylating agent
-MoA -e.g. |
Disrupt DNA function -> mutation, cell death:
-covalently adds alkyl group to guanine -cross link between 2 guanine e.g. cyclophosphamide (prodrug, CYP450) |
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Side effect of alkylating agents
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C Nv GHIB
nausea, vomit hair loss impaired wound healing GIT dysfunction cardiotoxicity hyperuricemia bone marrow suppression Acrolein (metabolite) = nephrotoxic ->hemorrhagic cystitis [mesna protect bladder] |
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Platinum compound - Cisplatin
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-water soluble
-platinum surrounded by 2 Cl- and 2 ammonia grps upon entering cell, Cl- dissociate to form active compound which react with H2O -this interacts with guanine causing intra/inter-strand linking |
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Methotrexate
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Antimetabolite: folate antagonist - interfere with thymidylate synthesis: binds to DHFR via having higher affinity than FH2
-inhibit purine and thymine synthesis --thus, prevent DNA synth and cell division |
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Side effects of methotrexate
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Bone marrow suppression
Immunosuppression -> infection Hair loss Nausea vomiting Anorexia Ulcers Stomach bleeding Liver toxicity Infertility @high dose: hyperuricemia, renal failure Highly teratotoxic |
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Base analogues
e.g. -MoA |
Pyrimidine: Fluorouracil
Purine: 6-mercaptopurine MoA: - -ve feedback [sufficient bases seem to be available] e.g. Fluorouracil inhibit thymidylate synthetase |
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Antimetabolites
-selectivity -act in which phase of cell cycle? |
-partially selective for tumor cells
=>toxic to all rapidly dividing cells -kills cells in S phase: when rapid cell proliferation occurs |
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Doxorubicin is a...
-MoA |
-cytotoxic antibiotic, anthracyclin
-binds to DNA, inhibit both DNA & RNA synth -inhibit topoisomerase II via stabilizing its complex with DNA, thus halts replication |
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Doxorubicin is good for...
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LLBB slot
leukemia lymphoma bladder breast stomach lung ovaries thyroid |
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Doxorubicin's severe side effect is...
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irreversible cardiomyopathy
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Mitoxanthrone
-MoA -good for... |
-MoA same as Doxorubicin
Good for: -metastatic breast cancer -leukemia -lymphoma -advanced prostate cancer (with prednisone) |
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Vincristine
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-antimitotic
-microtubule destabilizing agent =inhibit microtubule-polymerisation -prevent spindle formation, arresting at metaphase -can be used to synchronize cell replication so cancer cell may be more susceptible to other cancer drug at specific time |
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Docetaxel
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-antimitotic
-microtubule-stabilizing abent =stabilize microtubules in polymerised state -inhibit mitosis when the non-functional microtubules fails to form mitotic apparatus |
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Vincristine is for...
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leukemia
lymphoma testicular cancer |
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Side effect of vincristine
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-Neurotoxic in PNS & ANS
-mild to severe parasthesia -jaw pain -ataxia -muscle wasting -constipation -bone marrow suppression |
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Paclitaxel is for...
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O BEL HN
-ovarian = when given with cisplatin -breast, lung, head & neck, and esophageal cancer |
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Paclitaxel side effect
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bone marrow suppression
cardiovascular disorder GI disorder neurological disorder |
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Limitations of conventional cytotoxics
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-Variable therapeutic & toxic effect
-Low therapeutic index -tumor response difficult to measure -disease progression effect difficult to isolate -PK factors can be altered by changes of organ function and drug interaction -don't target cancer Genetic basis -no effect on invasiveness and metastasis characteristics -no effect on Angiogenesis -non-selectivity: target proliferation; selectivity based on fact cancer cells divide more rapidly |
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Cetuximab
-targets ... -used for... |
Tyr kinase inhibitor
-EGFR (HER1) rec monoclonal antibody blocker -rec normally incr proliferation & migration Uses: -metastatic colorectal tumor -head & neck tumor w wild type KRas |
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Herceptin
-targets... -used for -not eligible for patients with... |
Tyr kinase inhibitor
-HER2 rec --overexpression identified via IHC or karyotyping -breast cancer - this oncogene is amplified in 20-30% of invasive breast cancer -not for cardiac problem patients |
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bevacizumab (Avastin)
-MoA |
Tyr kinase inhibitor
-binds to VEGF-A, deprive from VEGFR -> inhibits angiogenesis -may also reduce metastasis - likely via reducing tumor cell migration |
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Imatinib
-MoA -for ... |
Tyr kinase inhibitor
-prevents ATP binding to Bcr-Abl [constitutively active kinase in CML] -> prevent downstrream phosphor necessary for downstream cell signalling -for Chronic myelogenous leukemia |
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Other methods of targeted therapy delivery being researched are...
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-Gene therapy (bcl2)
-Viral: adenovirus for ovarian cancer -Nanoparticles: small capsule to deliver drugs, can be targeted with antibodies or reach tumor via passive diffusion |
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Tumors derived from hormone-sensitive tissues can be hormone dependent. Growth of these tumors can be inhibited by...
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e.g. 65% breast cancer are hormone-dependent
-hormones with opposite action -hormone rec antagonist -agents inhibiting synth of stimulating hormone |
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Glucocorticoid
-used for... -MoA |
Hormone antagonist
-for leukemia lymphoma breast cancer -interfere DNA synth -> inhibit cell division |
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Ethinyl estradiol (synthetic estrogen)
-MoA |
Hormone antagonist
-recruit mammary cancer cells from compartment B to A [i.e. G0 to dividing] -this allows greater killing efficacy from cytotoxics |
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Tamoxifen
-MoA -used for... |
-competes with endogenous estrogen for rec
-antagonist and SERM (selective estrogen cell modulator) Uses: -adjuvant tx following surgery -post-menopausal metastatic breast cancer -inhibit estrogen-responsive genes -affects proliferation, apoptosis, DNA repair |
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Chemotx principle 1/5:
Use maximum tolerated doses of NCSA |
-NCSA operate on log cell kill basis
-dep on drug conc and cell density -peak conc critical to inflict max DNA dmg -needs to be at a level which exceeds cell's DNA repair capacity |
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Chemotx principle 2/5:
Employ prolonged exposure to CSAs |
-many tumors have 2-3d cycle time
-CSA should be admin'd for at least one cycle time -length of CSA exposure is more important than peak conc |
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Chemotx principle 3/5:
Use Chemotx as early as possible |
-tumor proliferation rates are commonly at a low level at time of diagnosis
-chemotx is most effective against subclinical tumors (microscopic) -adjuvant chemotx has been shown to be the more effective chemotx strategy |
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Chemotx principle 4/5:
Give chemotx in periodic pulses |
-tumor cells have inf repair mechanisms to normal cells, so recover more slowly
-chemotx is not v selective, relies on bone marrow recovering more quickly than tumor cells -Lenograstin (recombinant granulocyte colony stimulating factor) can be give to reduce neutropenia -Chemotx poulses are given when: -normal tissue has recovered -before full tumor recovery |
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Chemotx principle 5/5:
Give drugs in combination |
-simultaneously hit a no. of molecular targets
-broad range of activity for heterogenous tumor populations -compound anti-tumor effects with drugs that have non-overlapping toxicities and MoA -prevents or slows drug resistance -lower doses can be used with fewer side effects -chemotx and targeted tx have an additve effect and so are used together e.g. Herceptin and chemotx -exception is HRT --cytostatic and can antagonize the antiproliferative effects of chemotx |
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Mechanism of drug resistance by Cancer cells
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Enhanced inactivation (Scavenging)
-e.g. high intraC lvls of GSH which inactivates alkylating agents Reduced drug uptake -e.g. methotrexate enters cell via reduced folate carrier Incr'd removal of drug from cancer cell -incr'd transcription for proteins which act as carriers e.g. P-glycoprotein Drug target may change Cells develop superior repair mechanism Activation of pro-drugs (e.g. cyclophosphamide) may become defective Cells may incr their synth of precursor molecules e.g. purines & pyrimidines Cells may amplify gene expression for enz that is targeted |
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Remission from chemotx should last...
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>6mo before same drug is used again
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Remission from chemotx that is <6mo require...
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subseq use of non-cross resistant drugs for second line tx
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