Pharm 2 - Cancer/Chemotherapy Drugs

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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

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