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Main differences between normal and cancer cells
- Loss of cell growth
- decreased cell differentiation
- ability to invade surrounding tissue
- ability to establish new growth at ectopic sites (metastasis)
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Goal of chemotherapy
prevent cancer cells from multiplying, invading and metastasizing
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Why is cancer difficult to treat?
- <100 different tumor types
- cancer cells similar to normal cells
- Tumor eradication elicits an immune response
- Cancer drug toxicity
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Processes of controlling cell lifespan
- cell proliferation
- cell death
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Oncogene
gene overexpressed in cancer cells
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retinoblastoma pathway
- RB binds cyclin D and is phosphorylated by CDK4
- Structure opens and releases Cyclin D
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Mutation of RB Pathway
- Drives cell cycle much faster
- 20-30% of cancer cases
- 2nd major mutation
- high [CDK4]
- high [cyclin D]
- low [P16]
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p53
- transcription factor that functions as a "tumor suppressor"
- senses DNA problems and stops cell cycle
- -50% of cancer patients have mutated p53
- -causes resistance to some types of chemotherapy
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p53 mediated apoptosis
- Cancer drugs work by damaging DNA to induce p53 mediated apoptosis
- -mutated p53 = drug may not work
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Phase specific drug
Inhibits specific proteins or enzymes required for specific phases of the cell cycle
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Cell Cycle related drug resistance
Only a fraction of cells are in the specific phase for the drug to act
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Biochemical related drug resistance
- Altered metabolism
- Decreased uptake of drug into cell
- increased target
- defective apoptosis
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pharmacologic related drug resistance
- no receptors present
- poor perfusion of large solid tumors
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Multi Drug Resistance
- Decreased uptake mediated by P-glycoprotein
- Increased glutathions which neutralize alkylating agents, platinum compounds and antibiotics
- Decreased DNA topoisomerase II
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Drug Toxicity
- Normal tissues undergo damage from anti-cancer drug
- supplementary drugs allviate toxic effects or stimulate normal cells
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Dose Regimens
- Do not use 2 phase specific drugs targeting the same phase
- Combination therapy is more effective than monotherapy
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3 reasons combination therapy is better
- decrease resistance
- decrease toxicity
- target different cell cycle phases
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Five major classes of cancer drugs
- Alkylating Agents
- Antimetabolites
- Natural Products
- Miscellaneous Agents
- Hormones and Antagonists
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Five types of Alkylating Agents
- Nitrogen Mustards
- Ethyleneimines
- Alkyl sulfonates
- Nitrosoureas
- triazenes
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Two drug types that form adducts with DNA but do not alkylate
- platinum complex
- methylhydrazine
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Mechanism of Alkylating Agents
- Produce cytotoxic, mutagenic and carcinogenic effects by reacting with cellular DNA
- -N7 bond of guanine is susceptible to forming bonds with alkylating agents
- -Alkylated guanine mispairs with thymine
- Consequences trigger p53 mediated apoptosis
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Mechlorethamine***
nitrogen mustards
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Cyclophosphamide
prodrug which is activated by cytochrome p450 enzyme
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Cisplatin***
- Platinum coordination complex
- Very effective in testicular and ovarian cancer
- Toxic to kidney and GI tract
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Mechanism of Action for platinum coordination complex
- Enters cell via diffusion or active Cu2+ transporter
- Covalently binds to nucleophilic sites on DNA
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Antimetabolites
- Prevent biosynthesis or use of normal cellular metabolites
- Drug closely related to structure of metabolite it antagonizes
- S-phase specific
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3 classes of antimetabolites
- Folic Acid analogs
- Pyrimidine analogs
- Purine analogs
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Folic Acid Analogs
- Methrotrexate inhibits dihydrofolate reductases (DHFR)
- Undergoes conversion of polyglutamates which inhibit thymidylate synthesis
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Pyrimidine Analogs
- Drug analogs of A,C and T must countain sugar group
- -cannot be synthesized in the cell
- Halogenated Pyrimidines
- -Flourine
- -Prevents methylation of 5 position by thymidylate synthase (TS)
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Resistance to 5-FU results from
- Loss or decreased activity of enzymes necessary for activation of 5-FU
- Amplification of TS
- Mutation of TS that is not inhibited (most common)
- Insufficient concentrations of cofactor required to lock TS in inactive state
- -5,10-methylene tetrahydrofolate
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Cytarabine
- Analog of 2'-deoxycytidine
- Hinders rotation of pyrimidine base around nucleosidic bond and interferes with base stacking
- Potent inhibitor of DNA polymerase
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Purine Analogs
- Antiviral and anticancer
- Substitution of S for O creates compounds that are readily converted to nucleotides and incorporated into DNA
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Adrenocorical suppressants
mitotane
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Glucocorticoids
bind to the glucocoricoid receptor and activate gene expression that leads to apoptosis
used for acute leukemia in children and malignant lymphoma in children and adults
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Dexamethasone
- glucocorticoid
- suppress mitosis in lymphocytes
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Anti-Adrenal therapies for prostatic carcinomas
- competitive inhibitors of androgen receptor
- - AR blocker or Anti-androgens
- -Steroidal or non-steroidal
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Gonadotropin-Releasing Hormone Agonsists
- Cause surge in LH and FSH leading to negative feedback of gonadotropin release
- complete androgen blockage
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Combination therapy of androgen blockers and GnRH-agonists
Blocks androgens from adrenals and gonads
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Anti-Estrogen Treatments for Mammary Carcinomas
- Selective estrogen-receptor modulators (SERMs)
- Selective estrogen-receptor downregulators(SERDs)
- Aromatase Inhibitors (AIs)
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Selective estrogen-receptor modulators (SERMs)
- Tamoxifen
- partially inactivated transcription of estrogen genes
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Selective estrogen-receptor downregulators (SERDs)
- "Pure anti-estrogens"
- Binds 100x stronger than tamoxifen to ER
- -inhibits dimerization
- -increases degredation
- No transcription of estrogen genes will occur
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Aromatase Inhibitors (AIs)
- Aromatase is responsible for conversion of androstenedion and testosterone to estrogens
- 1st, 2nd and 3rd Generations
- 3rd Gen has 2 types
- -Type 1=binds irreversibly "suicide substrate"
- -Type 2=binds reversibly
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