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Pharm 2 - Cancer/Chemotherapy Drugs

STUDY
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Genetic Mutations
*permanent
*most are of minimal consequence
*98% have no effect
*mutations in regulatory genes can lead to loss of normal growth controls-->cancer
Oncogenes
typically signal cells to divide, but if mutated become overactive & tell cells to divide/grow when they normally shouldn't
Examples of Oncogenes
ras, myc, fos, bcr-abl, raf
Tumor suppressors
typically tell a cell to stop dividing, but if mutated won't stop cells from dividing
Examples of Tumor Suppressors
Rb, p53, WT1, p16, BRCA 1 & 2
Environmental factors that can cause DNA mutations & increase risk of cancer
tobacco, alcohol, tanning beds, nuclear reactors, certain viruses & bacteria, diet
Benign neoplasia
unlikely to kill if untreated; remains confined to one area
Malignant neoplasia
likely to kill if untreated; capable of invading surrounding tissues
Examples: leukemia, lymphoma, sarcoma, carcinoma (85% are carcinomas)
Characteristics of Cancer Cells
Uncontrolled proliferation
Immortalization
Dedifferentiation
Alterations in total DNA content
Mutations in oncogenes & tumor suppressor genes
Check point regulating proteins
Tumor suppressors
Why are cancer cells more susceptible to damage by chemicals?
They have lost their check point controls, so even w/ lots of cellular damage, they will continue dividing
3 targets of chemotherapeutic/antineoplastic agents
1) attack pathways that are regulated by tumor suppressor genes
2) design drugs that only affect mutated proteins
3) activate the immune system to destroy cancer
When are surgery & radiation most effective?
before cancer has metastasized (able to cure 33% of all cancer)
Tumor Cell determinants
different combinations of oncogenes & tumor suppressors are mutated in different cancers, thus each cancer type has different growth characteristics, therefore there's not just one agent that can cure all cancers
Log Kill Chemotherapy
-kills a constant PERCENTAGE of cancer cells regardless of their size (first order kinetics)
-can never kill ALL tumor cells
-# of log kills needed for trtmt depends on # of cancer cells in that patient
-3 log = 99.9% of cells dead
-4 logs = 99.99% of cells dead
Combination Chemotherapy
-provides maximal cell kill b/c 2 different drugs may have different effects
-2 drugs each w/ 3 log kill effectiveness together give 6 log kill effectiveness (synergistic)
-less chance for resistance
Chemotherapy Toxicity
-therapeutic index close to 1 = toxic to cancer & normal cells
-many drugs lack toxic specificity
-myelosuppression (bone marrow suppression) is usually the dose limiting toxicity
Class 1 agents cell cycle specificity
NO CELL SPECIFICITY: kill both normal & malignant cells to the same extent (radiation, mechlorethamine, carmustine)
Class 2 agents cell cycle specificity
CELL CYCLE PHASE SPECIFIC: target proliferating cells in preference to resting cells; only kill cells in one specific phase of cell
-most commonly used class
Class 3 agents cell cycle specificity
Cell cycle PHASE NON SPECIFIC: kill proliferating cells in preference to resting cells
-similar to class 2, but will kill proliferating cells in ANY/ALL phases of the cell cycle
What types of cancer are difficult to treat with chemotherapy?
slow growing cancers because Class 2 & 3 drugs are most effective against fast growing cancers (b/c they have lots of cell division)
3 common mechanisms for developing resistance to chemotherapy
1) mutation of target protein can change the drug binding site & block the drug's ability to bind
2) increased/decreased expression of targeted protein
3) increased/decreased expression of other proteins involved in transport or metabolism of drug
DNA synthesis inhibitors
Methotrexate (folate antagonist)
Thioguanine (purine antagonist)
5-FU (pyrimidine antagonist)
Hydroxyurea (ribonucleotide reductase inhibitor)
*These are all CLASS 2 AGENTS that act on S phase
DNA alkylating drugs
Mechlorethamine hydrochloride (nitrogen mustard)
Cyclophosphamide (nitrogen mustard)
Carmustine (nitrosurea drugs)
Cisplatin (platinum compounds)
Bisulfan
*these are CLASS 3 AGENTS that act on all phases of cell cycle
Topoisomerase inhibitors
Topotecan
Etoposide
*CLASS 2 -- S/G2 phase
DNA intercalating
Doxorubicin
*CLASS 2 -- S/G2 phase
Mitotic Inhibitors
Vincristine (tubulin polymerization inhibitor)
Paclitaxel (tubulin depolymerization inhibitor)
Hormones
Tamoxifen (anti-estrogens)
Flutamide (anti-androgens)
Monoclonal Antibodies
Rituximab (anti CD20)
Trastuzumab (anti HER2/neu)
Bevacizumab (anti VEGF receptor)
Panitumumab (anti EGF receptor)
Tyrosine Kinase Inhibitors
Imantinib (bcr-abl)
Erlotinib (EGF receptor)
Protease Inhibitor
Bortezimib (26S proteosome inhibitor)
MOA of methotrexate
binds & inhibits dihydrofolate reductase (DFHR) --> inhibits thymidylate synthesis & purine synthesis
Toxicities of methotrexate
*myelosuppression @ 4-7 days
*mucositis
*acute renal failure
MOA of thioguanine
inhibits PRPP amidotransferase -->inhibits purine synthesis
*requires activation by HGPRT
MOA of 5-Fluorouracil
inhibits thymidylate synthase (FdUMP form)
*Activated by THF
Toxicities of 5-FU
*hand-foot syndrome: tingling, numbness, pain erythema
*cardiac Sx (chest pain, ECG changes)
MOA of hydroxyurea
ribonucleotide reductase inhibitor-->blocks de novo DNA biosynthesis & DNA repair
toxicities of hydroxyurea
*teratogenic
*maculopapular rash
*headache, drowsiness, confusion
MOA of mechlorethamine hydrochloride
cross-link DNA-->inhibition of DNA synthesis & function
toxicities of mechlorethamine hydrochloride
*Bladder toxicity in 5-10% of pts
*amenorrhea w/ possible permanent sterility
Carmustine MOA
metabolites interfere w/ DNA, RNA & protein synthesis
toxicity of carmustine
*hepatotoxicity
*myelosuppression 4-6 weeks
*impotence, sterility, ovarian suppression, infertility, menopause
MOA of cisplatin
covalently binds DNA w/ preference to N7 position of guanine & adenint
*makes inter & intra strand cross links -->inhibits DNA synthesis & transcription
toxicity of cisplatin
*nephrotoxicity in 35-50%
*myelosuppression
*neurotoxicity & ototoxicity
MOA of bisulfan
*bifunctional alkylating agent
*interacts w/ thiol groups & nucleic acits do form DNA-DNA & DNA-protein cross links
toxicity of bisulfan
*increased risk of secondary malignancies, especially AML
*mucositis usually in first week
MOA of topotecan
topoisomerase I antagonist-->prevents religation
toxicity of topotecan
*headache &fever
-myelosuppression, nausea, vomiting, alopecia
MOA of etoposide
topoisomerase II antagonist -->prevents unwinding of double strand break
Toxicity of etoposide
*anorexia
-myelosuppression @ 10-14 days, alopecia, nausea, vomiting
MOA of doxorubicin
-intercalation leads to inhibition of DNA synthesis & transmission
-formation of toxic O2 free radicals causes single & double stranded breaks
-inhibits topoisom II to lesser extent
toxicity of doxorubicin
*cardiotoxicity -- presents 2-3 days as arrythmias, ECG changes, usually transient
MOA of vincristine
inhibits tubulin polymerization into microtubules
toxicity of vincristine
*Neurotoxic--antigrade & retrograde axon transport mediated by microtubules
MOA of paclitaxel
enhances polymerization & blocks depolymerization of microtubules
toxicity of vincristine
*hypersensitivity rxn
*neurotoxic
toxicity of tamoxifen
menopausal Sx, fluid retention, masculinization
toxicity of flutamide
hot flashes, decreased libido, impotence, gynecomastia, nausea, vomiting, feminization
MOA of rituximab
binds CD20 & inhibits cell cycle initiation
-found in 90% of NHL cells
MOA of trastuzumab
binds HER2 --> blocks normal growing
MOA of bevacizumab
directed against VEGF to block angiogenesis
MOA of panitumumab
anti-EGF (epidermal growth factor) receptor antibody used to treat EGFR-expressing metastatic colorectal cancer w/ disease progression
MOA of imantinib
binds bcr-abl oncogene (Philadelphia chromosome -- found in 90% of CML)
erlotinib
EGF receptor tyrosine kinase inhibitor -- useful in many cancers
bortezimib
inhibits proteasomes & reversibly inhibits chymotrypsin-like activity @ 26S proteasome -->activates apoptosis
toxicity of bortezimib
*infusion rxns
*neuropathies