1) surgery - prevention; diagnosis; cure; palliation

2) radiation - cure; palliation

3) chemotherapy - cure; palliation; adjuvant; neoadjuvant

4) biologic therapy - ex: immunotherapy

represents tumors in a rodent model; not solid tumors

cytotoxic drugs with first order kinetics

dose kills a constant proportion of cell population and not a constant number

inverse relationship between tumor cell number and curability

solid tumors - as they get bigger, growth factor decreases - outgrows blood supply

each dose may not kill a certain %

an anticancer agent that acts selectively on tumor stem cells when they are traversing the cell cycle and not when they are in the G₀ phase

ex: vinca alkaloids (M phase specific)

ex 2: Cytarabine (S phase specific)

most effective against tumors that are rapidly dividing

an anticancer agent that acts on tumor stem cells when they are traversing the cell cycle and when they are in resting phase

ex: alkylating agents - agents against DNA

includes: bis(chloroethyl)amines, nitrosoureas, alkyl sulfonate, ethyleneimine

similarities:

1) bis(choloroethyl)amines - form a cyclic ion that reacts with tissue NUCLEOPHILES = = alkylation tissue molecules (Does this on DNA = very important antitumor effect)

2) one possible mechanism of resistance involves a) DNA repair; b) decreased tumor uptake; c) increased incativation

3) toxicities: myelosuppression, GI, reproductive; carcinogenesis possible

alkylating agent

strong vesicant = don't give orally because it will cause blisters on skin = IV use

Hodgkin's disease (MOPP)

alkylating agent

prodrug that is converted in liver by P-450

effective immunosuppressant

toxicities: hemorrhagic cystitis - excretion of active metabolites - risk is reduced with HYDRATION

used in hematologic and solid tumors

alkylating agent

analog of cyclophosphamide

hemorrhagic cystitis

use mensa (sodium 2-mercaptoethane sulfonate)

CNS toxicity

use in testicular cancer

alkylating agent

use in chronic lymphocytic leukemia

alkylating agent

use in multiple myeloma

nitrosoureas

high lipid solubility; crossed BBB well

delayed myelosuppression (4-6 weeks delay)

use: brain tumors

nitrosourea

toxicities: myelosuppression in 20%; renal damage

use: pancreatic islet cell carcinoma

alkyl sulfonate

use: chronic myelogenous leukemia

alkylation of DNA

use in brain cancer

nonclassical alkylating agent

(DTIC)

triazene

use in malignant melanoma; Hodgkin's dz

(hexamethylmelamine)

alkylating agent

use: ovarian cancer

nonclassical alkylating agent - methylhdrazine derivative

multiple effects: inhibition of DNA, RNA, and protein synthesis

toxicities: 1) myelosuppression

2) CNS depression

3) disulfiram-like effect after alcohol

4) some monoamine ozidase inhibition - potential interactions

5) carcinogenic

Use: Hodgkin's dz (MOPP)

nonclassical alkylating agents

use: chronic lymphocytic leukemia

platinum compounds

binds to DNA and inhibits DNA synthesis/function (mechanism similar to alkylating agents); also binds to proteins

tox.: 1) nephrotoxicity (diminished by HYDRATION and DIURESIS) - use mannitol

2) myelosuppression, highly emetogenic, ototoxicity, peripheral neuropathy, electrolyte disturbances, anaphylactic-like rxns

use: testicular carcinoma, ovarian, bladder, lung, head, and neck cancers

platinum compound

analog with less renal and GI toxicity

dose-limiting myelosuppression

multiple uses: ovarian carcinoma

platinum compound

dose-limiting peripheral neuropathy

use: colorectal cancer

separated into folic acid analogs and purine & pyrimidine analogs

folic acid analogs include: methotrexate and premetrexed

purine analogs: 6-mercaptopurine and 6-thioguanine

pyramidine analogs: 5-fluorouracil, cytarabine, gemcitabine

treansported into target cell; inhibits dihydrofolate reductase; therefore, tetrahydrofolate formation is inhibited - this is involved in synthesis of thymidylate, purine nucleotides, and some amino acids - -> therefore you have decreased DNA, RNA, and protein synthesis

also converted in cells to polyglutamates (contributes to its activity)

Resistance: decrease cellular uptake

increase efflux

increase synthesis DHFR, altered DHFR

decrease formation of polyglutamates

administration via several routes (oral, IV, and intrathecal)

eliminated mainly by renal excretion

tox.: myelosuppression, GI, hepatic (with long-term Rx)

use: choriocarcinoma, breast, osteosarcoma

other uses: RA, psoriasis

folic acid analog (folinic acid, 5-formlytetrahydrofolate, Citrovorum factor)

antidote for OD of MTX

also used as part of high-dose MTX regimens (leucovorin rescue)

transported into cell and converted to polyglutamates

inhibits thymidylate synthase

also targets DHFR and enzymes involved in de novo purine nucleotide biosynthesis

*** folic acid and vitamin B12 supplementation "appear to reduce toxicity associated with pemetrexed while not interfering with clinical efficacy"

adverse effects: myelosuppression, GI, rash

use: mesothelioma, non-small cell lung cancer

similarities:

1) most are prodrugs - must be converted to nucleotides (base + sugar + phosphate)

2) most are also converted to inactive products

3) interferes with many biochemical Rx's (cytotoxicity), but interferes with DNA synthesis/function = important

4) MYELOSUPPRESSION

purine analog (-SH group instead of -OH)

active nucleotides interfere with multiple reactions in purine synthesis; also incorporated into DNA and RNA

other metabolic pathways include oxidation to 6-thiouric acid, catalyzed by xanthine oxidase

S-methylation, catalyzed by thiopurine-S-methyltransferase (TPMT)

TPMT activity varies in different patients due to genetic polymorphism = increased risk of toxicity in patients with low enzyme activity

important drug interaction with allopurinol which inhibits xanthine oxidase; reduce dose of 6-MP if taking allopurinol for gout

tox : myelosuppression, hepatotoxicity, immunosuppression

use: certain patients with leukemia

converted to active nucleotide(s)

1) also undergoes S-methylation by TPMT

2) deaminated to 6-thioxanthine (do not have to lower dose when using allopurinol)

use: certain patients with leukemia

nucleotide - dephosphorylated extracellularly; in cell = converted to active nucleotide

MECHANISM: inhibition of DNA synthesis/repair; inhibition of ribonucleotide reductase; incorporation into DNA; induction of apoptosis

tox. : myelosuppression, immunosuppression

use: chronic lymphocytic leukemia

incorp. into DNA; also decreases DNA synthesis/repair

some toxicities - myelosuppression, immunosuppresion

use: hairy cell leukemia

FdUMP (a deoxyribonucleotide) inhibitor of thymidylate synthase -> decrease thymidylate and DNA synthesis

5-FU incorp. into DNA and RNA

tox.: myelosuppression, GI, neurotoxicity

use: colorectal, breast

capecitabine converted into 5-FU

converted into 5-FU

tox.: myelosuppression, GI, hand-foot syndrome, (neurotoxicity)

use: breast cancer

cytosine (arabinoside; Ara-C)

inhibition of DNA synthesis/repair; incorp. into DNA; inhibition of DNA chain elongation

Tox: myelosuppression, GI, neurotoxicity

use: acute myelogenous leukemia

inhibition of ribonucleotide reductase, incorp. into DNA, inhibition of DNA syntehsis/repair

Tox. : myelosuppression, GI

use: pancreatic carcinoma, non-small cell lung cancer

ANTIBIOTIC

(actinomycin D)

binds to DNA = decrease RNA synthesis

given IV

Tox.: myelosuppression, GI, alopecia, tissue damage if extravasated

Use: Wilms' tumor

antibiotics

mech.: 1) inhibition of topoisomerase II

2) intercalation into DNA

3) free radical formation = cardiotox :(

4) binding to membranes

iv and hepatic metabolism (lower dose if there is hepatic dysfunction)

meylosuppression, nausea, stomatitis, alopecia, tissue damage if extravasated (necrosis), cardiotoxicity

Cardiotoxicity -  thought to be related to free radical damage - heart failure related to cumulative dose !! (pg 332)

acute form of toxicity = ECG abnormalities (arrhythmias); pericarditis-myocarditis possible

if you have to continue this drug, give dexrazoxane (an iron chelator) to decrease the toxicity (after cumulative dose of 300 mg/m²)

antibiotic

mixture of glycopeptides; binds to DNA and causes strand breaks (formation of iron complex and generation of free radicals)

eliminated mainly in urine

tox.: ***1)PULMONARY : cough and dyspnea --> pulm. infiltrate --> pulmonary fibrosis (increased risk with old age and increasing cumulative dose)

2) skin rxns: tenderness, erythema

3) allergic reactions (anaphylaxis)

4) relatively bone marrow sparing

use: testicular carcinoma, lymphomas

antibiotic

reduced to an alkylating agent

tox.: nausea, myelosuppression, hemolytic uremic syndrome, pulmonary toxicity

use: squamous cell cancer of anus (adenocarcinoma of stomach/pancreas?)

plant derived drug: vinca alkaloid

mitotic inhibitor: binds to tubulin and inhibits polymerization to microtubules -->mitotic arrest

tox.: 1) mild BM suppression

2) neurotoxicity = peripheral neuropathy, consitipation

3)irritation with extravasation

4) alopecia

plant derivative: vinca alkaloid

binds to tubulin and inhibits formation of mitotic spindle

tox.: 1) severe myelosuppression ("vinblastine blasts bone marrow")

2) nausea; vomitting

3) alopecia

plant derivative: taxane

binds microtubules and promotes polymeration --> inhibition of mitosis (remember to contrast with vinca alkaloids)

tox. : 1) hypersensitivity reaction, myelosuppression, peripheral neuropathy, arrhythmias

use: ovarian and breast cancer

(new form of the drug for breast cancer tx = bound to albumin and it has decreased toxiticy

plant derivative: taxane

binds microtubules and promotes polymeration --> inhibition of mitosis (remember to contrast with vinca alkaloids)

tox. : hypersensitivity reaction, myelosuppression, peripheral neuropathy, arrhythmias

use: breast cancer

plant derivative: podophyllotoxin - - epipodophyllotoxin

inhibits topoisomerase II - -> DNA strand breaks

tox. : myelosuppression, alopecia, N&V, allergic reactions; leukemias have been reported

use: testicular carcinoma; small cell lung cancer

Used only outside the US, but now there are package inserts for it (so now used in US)

plant derivative: podophyllotoxin - - epipodophyllotoxin

inhibits topoisomerase II - -> DNA strand breaks

tox. : myelosuppression, alopecia, N&V, allergic reactions; leukemias have been reported

plant derivative: camptothecins

inhibits topoisomerase I causing DNA damage

tox: myelosuppression (neutropenia), GI

use: ovarian carcinoma, small cell lung cancer

plant derivative: camptothecins

inhibits topoisomerase I causing DNA damage

rxn involving glucuronyl transferase, but enzyme often has polymorphisims, requiring one to reduce doses of this drug and do genetic testing before administration

tox: myelosuppression, diarrhea, N&V

use: colorectal cancer

bacterial enzyme (use E Coli)

catalyzes hydrolysis of circulating L-asparagine to aspartic acid and NH₃ --> depletes asparagine in certain leukemic cells --> decrease protein synthesis

tox. allergic reactions, hepatotoxicity, clotting factor changes --> bleeding or clotting, pancreatitis, hyperglycemia

use: acute lymphocytic leukemia

this is a fusion protein; part of signaling pathway that leads to cell proliferation

unlike other receptors, does NOT need ligand to stimulate it; consitutively active in CML cells

(Gleevec) - inhibits Bcr-Abl tyrosine kinase --> inhibits proliferation and induction of apoptosis

also inhibits some other receptor tyrosine kinases

hepatic CYP metabolism

tox.: N&V; diarrhea; fluid retention/edema; muscle cramps; anemia; neutropenia; thrombocytopenia; hepatotoxicity; drug interactions

use: chronic myeloid leukemia; gastrointestinal stromal tumor

inhibit Bcr-Abl and some other kinases

may be used if become resistant to imatinib

use: CML

inhibit Bcr-Abl and some other kinases

may be used if become resistant to imatinib

use: CML

growth factor receptor inhibitors

monoclonal antibody that binds to extracellular domain of epidermal growth factor receptor (EGFR) --> inhibit downstream receptor signaling (preventing cell proliferation and angiogenesis)

EGFR is over expressed in some tumors

some genetic consideration: K-RAS --> mutation renders this drug ineffective

tox: infusion reactions, rash (acne type), hypomagnesemia, interstitial lung disease

use: head and neck cancer, colorectal cancer

growth factor receptor inhibitors

monoclonal antibody that binds to extracellular domain of epidermal growth factor receptor (EGFR) --> inhibit downstream receptor signaling (preventing cell proliferation and angiogenesis)

EGFR is over expressed in some tumors

some genetic consideration: K-RAS --> mutation renders this drug ineffective

tox: infusion reactions, rash (acne type), hypomagnesemia, interstitial lung disease

use: colorectal cancer

(enters cytoplasm) inhibits the tyrosine kinase domain of EGFR --> inhibits receptor signaling

oral; hepatic metabolism

tox: diarrhea, rash, interstitial lung dz; potential drug interactions

use: non-small cell lung cancer

(enters cytoplasm) inhibits the tyrosine kinase domain of EGFR --> inhibits receptor signaling

oral; hepatic metabolism

tox: diarrhea, rash, interstitial lung dz; potential drug interactions

use: non-small cell lung cancer; pancreatic cancer

monoclonal antibody binds VEGF --> prevents VEGF action on its receptors

tox: hypertension, infusion reaction, GI perforation, wound healing complications, bleeding, arterial thromboembolic events, proteinuria

use: colorectal cancer, non-small cell lung cancer

inhibit multiple tyrosine kinases, including some VEGF receptors, some PDGF, and others

oral, metabolized by CYP

adverse: hypertension, fatigue, bleeding, hand-foot syndrome (unique to this drug)

use: renal cell cancer, hepatocellular cancer

inhibit multiple tyrosine kinases, including some VEGF receptors, some PDGF, and others

oral, metabolized by CYP

adverse: hypertension, fatigue, bleeding;  cardiac dysfunction, possibly with heart failure (decrease ejection fraction) (unique to this drug)

use: renal cell cancer, gastrointestinal stromal tumor

differentiating agent: retinoic acid derivative:

all trans-retinoic acid

induction of differentiation to cells that cannot proliferate

tox: vitamin A toxicity, retinoic acid syndrome (fever, increase white count, weight gain, pulmonary problems)

use: acute promyelocytic leukemia

differentiating agent

induction of differentiation

tox: QT prolongation, arrhythmias, syndrome similar to retinoic acid syndrome

use: actue promyelocytic leukemia

proteasome inhibitor: ubiquinated proteins enter proteasome and get broken down - so this drug saves some important proteins (but we don't really know which ones)

tox: peripheral neuropathy, GI, hypotension, thrombocytopenia, neutropenia

use: multiple myeloma

substitued urea

inhibits ribonucleotide reductase (which takes ribonucleotides to deoxy ribonucleotides = DNA synthesis) --> decreased DNA synthesis

tox: myelosuppression, GI, dermatologic reactions (Rash, ulcerations)

use: chronic myelogenous leukemia

CD 20 antigen

use: B cell non-Hodgkin's lymphoma

HER-2/ neu

BREAST CANCER

tumor cells increase p-glycoprotein

= increased efflux of drug from tumor cells