Module 6 Pharmacology

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Cancer is characterized by...?: 1. uncontrolled cell proliferation
2. decreased cellular differentiation
3. invasion of surrounding tissue
4. metastasis
Drugs used in cancer chem can be classified according to...?: 1. MOA
-- alkylating agents

2. source
-- plant alkyloids

3. activity during the cell cycle
-- cell cycle non-specific
-- cell cycle specific
Cell cycle of cancer cells?: Go = differentiation; resting phase

G1 = synthesis of cmpds needed to synth DNA
-- (18-30h)

S = DNA replication and repair
-- chrom double
-- 16-20h

G2 = synth of molecules needed for mitosis
-- 2-10h

M = mitosis
-- 0.5 - 1h
Cell cycle (phase) nonspecific drugs (CCNS) are drugs which...?: Kill at any phase
Killing is dose-dependent

1. can work at any step in the cell cycle, including Go

2. cells are more susceptible in late G1 and S b/c polynucleotides are more susceptible to alkylation in the unpaired state than in helical form

3. toxicity usually expressed when cells enter S phase and progression through cell cycle is blocked

4. Example: DOXORUBICIN
-- intercalates into DNA
-- DNA strand scission (single and double strand breaks) via inhib of TopoII
-- cells die in G2
What are the CCNS drugs categories?: 1. polyfxnal alkylating agents

2. nitrosoureas alkylating agents

3. platinum alkylating agents

4. other alkylating agents

5. anthracycline antibiotic drugs

6. camptothecins

7. glucocorticoids
Name the CCNS polyfxnal alkylating agents: mechlorethamine
tiotepa
cyclophosphamide
melphalan
chlorambucil
busulfan
Name the CCNS nitrosoureas alkylating agents.: carmustine (BCNU)

lomustine (CCNU)

Also act in Go which is the reason that they are used to treat primary tumors in the CNS
Name the CCNS platinum alkylating agents.: cisplatin
carboplatin
Name the CCNS "other" alkylating agents.: procarbazine
temosolamide
Name the CCNS antibiotic drugs: dactinomycin
mitomycin-C
Name the CCNS anthracycline antibiotic drug: doxorubicin (aka hydroxydaunorubicin)
Name the CCNS camptothecin: topetecan
Name the CCNS glucocorticoid: prednisone
Cell cycle specific drugs are drugs which...?: -- Kill in specific phases of the cell cycle
-- Prolonged exposure causes greater killing (time-dependent)
-- Increasing dose does NOT cause more killing

1. Inhibit cell division by acting during a specific phase of the cell cycle
-- cells in the sensitive phase of the cycle are killed

2. These drugs are most effective in hematologic cancers and tumors w/ a relatively large number of cells in the "growth fraction"
Which drugs suppress the G1 phase?: G1 = 40% of cell cycle

CORTICOSTEROIDS suppress mitosis and cause apoptosis of non-dividing cells
List the drugs which work during the S phase.: S phase = 40% of cell cycle
-- ANTIMETABOLITES work here

5-fluorouracil (5-FU)
6-mercaptopurine (6-MCP)
6-thioguanine (6TG)
methotrexate
gemcitabine
capecitabine
cytarabine (Ara-C)

Non-antimetabolite:
hydroxyurea
5-FU?: 5-fluorouracil

Inhibits thymidine synthetase
6-MP and 6-TG?: 6-mercaptopurine and 6-thioguanine

Inhibit purine synthesis
methotrexate?: inhibits DHF reductase
gemcitabine?: inhibits ribonucleatide reductase
capecitabine?: p.o.

converts to 5-FU
cytarabine?: Ara-C

inhibits DNA polymerase
hydroxyurea?: inhibits ribonucleotide reductase
List the drugs which work during the G2 phase.: G2 phase = 18% of cell cycle

ANTIBIOTIC:
bleomycin

EPIPODOPHYLLOTOXIN:
etoposide
bleomycin?: fragmentation of DNA

cells accumulate in G2
etoposide: stabilizes the bond btwn TopoII and DNA
-- TopoII is inhibited so double stranded DNA breaks remain
-- DNA is degraded
-- blocks in late S-G2

**TopoII is needed for the completion of mitosis
List the drugs which work during late G2-early M phase.: VINKA ALKALOIDS:
1. vincristine
2. vinblastine
vincristine and vinblastine?: bind to tubulin and prevent assembly of microtubules
-- cells arrest in late G2 b/c mitotic filaments cannot form

However, on the BJE, these vinca alkaloids act in the M phase
List the drugs which work during the M phase: M phase = 2% of cell cycle = mitosis

TAXANES:
1. paclitaxel

VINKA ALKALOIDS:
1. vincristine
2. vinblastine
**BJE
General toxicity of antineoplastic drugs?: 1. rapidly prolif tissues suffer the most damage

2. myelosuppression is the most common dose-limiting toxicity

3. selective organ toxicities
What toxicities are associated w/ antineoplastic drugs in rapidly proliferating tissues?: GI MUCOSA
-- n/v
-- stomatitis

HAIR FOLLICLES
-- alopecia - hair will grow back
-- no regrowth after radiation

OVARY/TESTIS
-- amenorrhea
-- azoospermia

BONE MARROW
-- myelosuppression (BM suppression)
What is the most common dose-limiting toxicity for antineoplastic drugs?: Myelosuppression
How do we treat anemia due to antineoplastic drugs?: Symptom: fatigue, SOB

i.v. or s.c.

Epoetin alfa
How do we treat thrombocytopenia due to antineoplastic drugs?: thrombocytopenia = hemorrhage

OPREVEKIN (IL-11) megakaryocyte growth factor

Recombinant human thrombopoietin is in clinical trials
How do we treat leukopenia due to antineoplastic drugs?: leukopenia = infections, fever
(PMN < 1000)

Antibiotic drugs + Colony stimulating factors (CSF)

FILGRASTIM - granulocyte CSF
SARGRAMOSTIN - granulocyte/macrophage CSF

Leukopenia can demonstrate rapid recovery (14-21 days) or delayed recover (50+ days)

The nadir PMN count during a cycle of chemo is the most important value
What is leucovorin?: Folinic acid -- A rescue treatment for bone marrow

Normal cells can take up leucovorin, but tumor cells cannot

Great for myelosuppression.
Name the drug that has selective toxicity for the heart.: doxorubicin
Name the drug that has selective toxicity for the lungs.: bleomycin
Name the drug that has selective toxicity for the kidneys.: cisplatin
Name the drug that has selective toxicity for the urinary bladder: cyclophosphamide
Why is there a need for combo chemotherapy?: Treatment of several drugs w/ different MOA's prevents the development of resistant clones of cancer cells.
What is primary or natural cancer chemo resistance?: resistance present prior to exposure to drugs
-- colon cancer
-- non-small cell lung cancer
Examples of acquired resistance during chemo?: Due to genetic changes.

1. loss of p53 tumor suppressor gene

2. overexpression of BCL-2 gene = prevents apoptosis

3. overexpression of genes MDR1 and Pgp170 which code for drug efflux pumps
-- these genes cause cross-resistance btwn different classes of drugs
-- taxanes -- paclitaxel
-- vinca alkaloids -- vincristine

4. Pharmacokinetic resistance
-- treatment with other drugs which induce CYP450
Name the alkylating agents.: mechlorethamine
chlorambucil
melphalan
cyclophosphamide
thiotepa
busulfan
carmustine (BCNU)
lomustine (CCNU)
temozolamide
procarbazine
cisplatin
carboplatin
MOA of alkylating agents?: 1. They damage DNA via:
-- cross-linking (bifunctional drugs w/ two reactive groups) OR
-- single-strand breaks (monofunctional drugs w/ one reactive group)

2. Primary site of DNA alkylation is the N7 position; O6 of guanine is also attacked

3. Alkylation of DNA:
-- inhibits synth of DNA, RNA, and proteins
-- causes misreading of DNA
Alkylating agents toxicity?: 1. myelosuppression and immunosuppression = dose limiting toxicity

2. NAUSEA & VOMITING with 30-60 minutes of treatment
-- must pre-treat w/ 5-HT3 blockers such as ondansetron

3. TERATOGENIC & CARCINOGENIC
-- secondary leukemias
-- most common cancer caused by chemo is AML

4. Pulmonary fibrosis (rare)
-- bisulfan, chlorambucil
-- melphalan, nitrosoureas

5. amenorrhea and azoospermia

6. hepatic venoocclusive disease
-- chemo obliterates brances of small hepatic veins
-- can lead to portal HTN
What drugs are used to treat solid tumors and hematologic cancers?: **usually in combo w/ other antineoplastic drugs -- ALKYLATING AGENTS

1. Nitrogen mustards
-- mechlorethamine
-- chloramucil
-- mephalan
-- cyclophosphamide

2. Thiotepa

3. Busulfan

4. Nitrosoureas
-- carmustine
-- lomustine

5. temozolamide

6. procarbazine

7. platinum containing drugs
-- cisplatin
-- carboplatin
Which of the nitrogen mustard drugs can cause secondary leukemias?: mephalan
Side-effects of cyclophosphamide?: 1. myelosuppression

2. immunosuppression = used in organ transplantation

3. highly emetic

4. Acrolein metabolite causes
-- hemorrhagic and non-hemorrhagic cystitis
-- adequate hydration and frequent urination req'd to prevent GU damage

5. SIADH -- can cause water intake since water intake is increased to prevent GU damage
What must you give with cyclophosphamide to prevent GU damage?: Mesna

A free-radical scavenger that is rapidly cleared by the kidneys
-- binds the acrolein metabolite of phosphamide
Tiotepa therapeutic use?: Special application because:

1. Injected into urinary bladder
-- treat superficial bladder cancers

2. Injected into peritoneal cavity

3. Injected into CSF
-- CNS metastases
Busulfan therapeutic use?: Kill bone marrow prior to transplant
Busulfan S/E's?: bronze hyperpigmentation

pseudo-Addison's disease

pulmonary fibrosis

hepatoveno-occlusive disease
Nitrosoureas therapeutic use?: i.v.

Carmustine (BCNU)
Lomustine (CCNU)

Cross BBB and used to treat CNS tumors
Temozolamide therapeutic use?: Crosses the BBB and does NOT need bioactivation

Used to treat primary and secondary brain tumors
Procarbazine therapeutic use?: p.o

Inhibits synth of DNA, RNA, and proteins
-- causes chromosomal breaks
Cisplatin, carboplatin toxicity?: i.v.

1. Highly emetic
-- pretreat w/ 5-HT3 blocker + dexamethasone

2. nephrotoxic - pre- and post-treatment hydration w/ 0.9% saline decreases toxicity
-- Carboplatin exhibits less renal and GI toxicity

3. high frequency hearing loss

4. neurotoxicity
-- sensory neuropathy
Name the antimetabolites and their general MOA?: methotrexate
5-FU
capecitabine
cytarabine (Ara-C)
gemcitabine
azacitidine
6-MP
6-TG
pentostatin

structural analogs of the naturally occurring baases which are req'd for DNA/RNA synth
Methotrexate MOA?: structurally similar to folic acid

Forms highly active polyglutamate compounds which persist in cancer cells

1. reversible inhibition of DHF reductase prevents the synthesis of THF

2. lack of THF decreases synth of thymidylate, purine nucleotides, and serine/methionine

3. Also inhibits several folate-dependent enzymes involved in synth of both purines and thymidilate. Enzymes are:
-- thymidilate synthetase
-- glycinamide ribonucleotide formyltransferase (GARFT)
Methotrexate toxicity?: MYELOSUPPRESSION
-- treat w/ leucovorin

NEPHROTOXICITY
1. excreted unchanged in urine
-- sulfonamides, NSAIDs, and COX-2 inhibitors decrease clearance

2. Relatively insoluble in acidic urine, so large doses can lead to precip of drug w/in renal tubule
-- pt should be well-hydrated so urine can be made alkaline

3. Large doses cause mucositis and hemorrhagic enteritis

4. Causes transient elevations AST, and ALT
-- chronic trtmt w/ small doses has led to hepatic fibrosis

5. Intrathecal injection can cause arachnoiditis (stiff neck, headache, fever)
Which of the antimetabolites are pyrimidine (C, U, T) analogs?: 5-FU
capecitabine
cytarabine (Ara-C)
gemcitabine
azacitidine
5-FU therapeutic use?: i.v.

topical for actinic keratoses and basal cell cancers
5-FU MOA?: 1. The metabolite F-dUMP irreversibly inhibits thymidylate synthetase

2. lack of thymidylate prevents DNA synth = "thymineless death"

3. 5-fluorouridine triphosphate is incorporated into mRNA and prevents the normal translation of mRNA
5-FU toxicity?: 1. Inactivated by the enzyme dihydropyrimidine dehydrogenase (DpD)--> some pts cannot inactivate b/c they lack this enzyme

2. myelosuppression

3. stomatitis, mucositis, diarrhea

4. hyperpigmentation

5. photosensitivity

6. "hand-foot" syndrome - painful erythematous desquamation of the palms and soles
Capecitabine therapeutic use?: Oral 5-FU

Affects DNA/RNA synth
Capecitabine MOA?: converted to 5-FU inside cells by the enzyme thymidine phosphorylase
-- enzyme expressed more in tumor cells than in normal cells
Capecitabine toxicity?: less than 5-FU given i.v.

1. myelosuppression
2. hand-foot syndrome, dermatitis
3. hyperbilirubinemia
4. cardiac toxicity
Cytarabine therapeutic use?: Used for induction and relapse of AML
Cytarabine MOA?: 1. phosphorylated ara-CTP inhibits DNApol

2. phosphorylated ara-CTP is incorporated into DNA and RNA
Cytarabine toxicity?: 1. mucositis
2. reversible cerebellar toxicity
3. conjunctivitis
4. cholestatic jaundice
Gemcitabine MOA?: Gemcitabine di- and triphosphates inhibit ribonucleotide reductase
-- depletes cell of the deoxyribonucleoside triphosphates needed to synth DNA

Addition of gemcitabine triphosphate to the growing DNA strand results in chain termination
Gemcitabine toxicity?: myelosuppression
Azacitidine MOA?: 1. methylation of DNA turns off tumor suppressor genes

2. Azacitidine inhibits the enzyme DNA methyltransferase and thus turns ON the tumor suppressor genes

3. Incorporation into mRNA
Azacitidine toxicity?: myelosuppression
What are the purine (A, G) analogs?: 6-MP
6-TG
pentostatin
6-MP and 6-TG MOA?: p.o.

1. The enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT) converts 6-MP and 6-TG to the nucleotide form which inhibits many nucleotides in the purine nucleotide pathway

2. Net effect: inhibition of synth of DNA, RNA, and glycoproteins
How does resistance to 6-MP and 6-TH occur?: HGPRT decreases its activity
6-MP and 6-TG toxicity?: 6-MP is degraded by xanthine oxidase
-- allopurinol (antigout Rx) inhibits xanthine oxidase
-- toxicity accentuated
-- 6-TG is not metabolized by xanthine oxidase

MYELOSUPPRESSION
Pentostatin MOA?: Irreversible inhibitor of adenosine deaminase
Pentostatin toxicity?: myelosuppression

immunosuppression
What are the classes of antineoplastic drugs that are natural products?: Antitumor antibiotics

Epipodophyllotoxins

Camptothecins

Vinka alkyloids

Taxanes
What are the antitumor antibiotics?: bleomycin
dactinomycin
mitomycin-C
doxorubicin
Name the epipodophyllotoxins.: etoposide
Name the camptothecins.: topotecan
Name the vinka alkyloids.: vincristine
vinblastine
Name the taxanes.: paclitaxel
Bleomycin MOA?: i.v i.m. s.c intracavitary

1. after binding DNA, oxygen free radicals are formed which cause single and double-stranded breaks

2. DNA synth halts

3. Fragmentation of DNA leads to chrom abnormalities

4. Cancer cells accum in Go
Bleomycin toxicity?: 1. lethal anaphylactic rxns, espec in pts w/ lymphoma

2. fever and chills w/in 48 hrs

3. PULMONARY FIBROSIS
-- begins w/ dry cough, fine rales, and diffuse basilar infiltrates on CXR
-- progresses to PF

4. Hyperpigmentation of elbows and knees; hyperkeratosis of palms

NO BM DEPRESSION!!
Dactinomycin MOA?: 1. intercalates into dsDNA btwn G-C pairs

2. DNA replication is little affected, but DNAdepRNAsynth is impaired so protein synth is blocked
Dactinomycin toxicity?: 1. myelosuppression

2. immunosuppression

3. radiation "recall" -- skin inflamm at previously irradiated sites
Mitomycin-C MOA?: alkylation cross-links DNA, especially in hypoxic tumor cells
Mitomycin-C toxicity: severe myelosuppression
What's so special about doxorubicin?: One of the most widely used antineoplastic drugs

Used in combo w/ one or more other drugs to treat:

1. Carcinomas -- ovary, testicle, thyroid, lung, breast, endometrium

2. Sarcomas -- osteosarcoma, Ewing's sarcoma, neuroblastoma, rhabdomyosarcoma

3. Hemotologic cancers -- acute leukemia, Hodgkin's disease, NHL, and multiple myeloma

Anthracycline
Doxorubicin MOA?: 1. intercalation into DNA blocks synth of DNA and RNA

2. causes DNA strand scission via TopoII

3. Alters ion transport through mbrns

4. Causes generation of semiquinone and oxygen-free radicals
Doxorubicin toxicity?: HEART -- free radical damage
1. acute -- PVCs, transient changes in ST segment and Twave
2. chronic -- cumulative, dose-related cardiomyopathy causing heart failure
-- total cumulative dose determines likelihood pt will develop cardiac daage

myelosuppression

stomatitis

radiation recall

alopecia
Etopiside MOA?: Cell-cycle specific! Late S - G2

Remember:
-- TopoI cuts and religates ssDNA
-- TopoII does the same for dsDNA
-- TopoI and II are necessary for DNA replication and RNA transcription
-- TopoII is needed for completion of mitosis

1. etopiside stabilizes the bond btwn DNA and TopoII

2. TopoII is inhibited so the dsDNA breaks remain; DNA is degraded
Etoposide toxicity?: 1. dose-limiting myelosuppression

2. anaphylaxis

3. fever

4. hypo- or hypertension

5. secondary leukemias
Topotecan MOA?: Cell cycle NON specific!

Inhibition of TopoI causes DNA damage
Topotecan toxicity?: myelosuppression

occasional diarrhea
Vincristine & vinblastine MOA?: "spindle poisons"

1. microtubules which form mitotic spindle are heterodimers consisting of α- and β-tubulin

2. mitotic spindles separates the duplicate sets of chrom during cell division

3. microtubules said to have "dynamic instability" b/c they are constantly remodeling
-- involves constant incorp of free dimers and simultaneous release of dimers into soluble tubulin pool

4. vinca alkaloids bind to the dimeric tubulin to prevent further polymerization

5. microtubules which have already been formed, depolymerize

6. Net effect is mitotic arrest in METAPHASE
Vincristine & vinblastine toxicity?: VINBLASTINE
1. dose-limiting myelosuppression

VINCRISTINE
1. little myelosuppression
2. dose limiting neurotoxicity in ALL patients
-- loss of tendon reflexes
-- paresthesias in "stocking-glove" pattern
-- autonomic dysfxn = constipation, orthostatic hypotension
Paclitaxel MOA?: "spindle poison"

1. promotes assembly of microtubules and stabilizes them to prevent depolymerization
-- prevents dynamic instability

2. phosphorylation of teh antiapoptosis gene Bcl-2
-- oncogene which suppresses programmed cell death
-- phosph turns OFF Bcl-2
Paclitaxel toxicity?: 1. myelosuppression

2. peripheral neuropathy

3. myalgias

4. pretreatment w/ a corticosteroid decreases the severity of other effects including:
-- anaphylaxis
-- peripheral edema
-- epihora (excessive tearing)
-- erythematous pruritic maculopapular rash
-- pathological nail changes
2 examples of adjuvant therapy via hormonal drugs?: 1. corticosteroids used to treat lymphoid tumors
-- cause apoptosis in non-dividing cells

2. Estrogen receptor antagonist tamoxifen used to treat breast cancer which is estrogen receptor (+)
What is an Oncotype DX?: 1. Expression of panel of 21 genes is quantified by analysis of formalin-fixed, paraffin-embedded breast tumor tissue

2. Diagnostic assay quantifies likelihood that breast cancer will reoccur = Recurrence Score = 1-100

3. Assay also reveals if cancerous tissue expresses estrogen or progesterone receptors and the Her2/neu (ErbB-2) epidermal growth factor receptor

4. Pts w/ tumors expressing estrogen receptors can be treated w/ antagonist TAMOXIFEN for first 5 yrs.
-- Then switched to aromatase inhibitor, LETROZOLE

5. Expression of HER2/neu receptor is assoc w/ lack of a clinical response to trtmt w/ cytotoxic or hormonal agents
Hydroxyurea MOA?: Acts in S phase by inhibiting enzyme ribonucleotide reductase

Depletion of deoxynucleoside triphosphates prevents DNA synthesis
Hydroxyurea toxicity?: myelosyppression
How else is hydroxyurea used?: Used to treat sickle-cell disease.

Fetal Hb (HbF) is normal in pts w/ sickle cell
-- hydroxyurea turns on the HbF gene in adults
-- presence of HbF prevents RBC sickling
L-asparaginase therapeutic use?: Leukemia therapy
L-asparatinase MOA?: hydrolyzes serum asparagine which is an essential aa for leukemia cells
-- normal cells can synth l-asparagine
Imatinib (Gleevec) MOA?: Blocks binding of ATP to Bcr-Abl tyrosine kinase
-- inhibits phosphorylation of the kinase substrate
-- kinase essential for prolif and survival of abnormal white cells causing CML

**CML common in pts w/ t(9;22) Philadelphia chromosome which codes for fusion oncoprotein Bcr-Abl which is a tyrosine kinase
Bortezomib MOA?: 1. proteasome 26S causes proteolysis of the inhibitor (IκB) of nuclear factor kappa B (NF-κB)

2. NF-κB upregulates DNA transcription, cell survival, and inhibits apoptosis

3. Bortezomib inhibits the activity of the 26S proteosime and thus prevents degradation of IκB which in turn enhances apoptosis by preventing action of NF-κB
Bortezomib therapeutic use?: Used to treat multiple myeloma (plasma cell cancers)
What are the anti-neoplastic immunomodulating agents?: levamisole

thalidomide
Levamisole therapeutic use?: 1. restores depressed immune fxn in B cells, T cells, monocytes, and macrophages

2. Potentiates the antineoplastic effects of 5-FU in pts w/ colon cancer
Thalidomide therapeutic use?: inhibits formation of new blood vessels
-- teratogenic!!
Name the antineoplastic monoclonal antibodies?: trastuzumab

cetuximab

retuximab
Trastuzumab therapeutic use?: used to treat breast cancer in patients who have tumors positive for HER2/neu
-- about 30% of pts w/ breast cancer have this oncogene
Trastuzumab toxicity?: can cause cardiac dysfxn, especially if given w/ doxorubicin
Cetuximab MOA?: blocks HER1 EGFR

-- 60-75% of colorectal cancers express this epidermal growth factor receptor which serves to cause cell prolif, survival, and angiogenesis
Rituximab MOA?: binds to the CD20 Ag expressed on all malignant B lymphocytes

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