antitumor agents

nitrogen mustards MOA

at alkaline pH, the chloroethylamine rearranges to the aziridine intermediate which is attacked by the N-7 position of guanine residues in DNA

a second rearrangement allows the mustard to attack a second guanine (cross linking)

Mechlorethamine

most reactive nitrogen mustard

IV ONLY

ADR: hearing loss, vertigo, skin blisters (when handling solutions)

Melphalan (L-PAM)

N-mustard

used IV and oral

ADR: bisulfan lung

Estramustine

N-mustard

orally active

fairly well tolerated

Chlorambucil

N-mustard

oral activity

least toxic of alkylating agents

ADR: dermatitis, hepatitis, sterility, pulmonary fibrosis (rare)

Cyclophosphamide

N-mustard

metabolized in liver by CYP450

oral and IV

ADR: hemorrhagic cystitis (may be dose limiting)

MENSA

reduces bladder toxicity of cyclosporines

Ifosfamide

N-mustard

structurally similar to cyclophosphamide

IV only

ADR: bladder toxicity, CNS toxicity at high doses

Carmustine

chloroethyl nitrosourea

alkylating and carbamoylating

IV only

ADR: bisulfan lung, brown stain to skin

Lomustine

chloroethyl nitrosourea

alkylating and carbamoylating

oral only

ADR: pulmonary fibrosis, CNS toxicity

Streptazocin

methyl nitrosourea

carbamoylates proteins

IV and IA

ADR: nephrotoxicity (DL), induces diabetes

Busulfan

bis-alkylator

oral and IV

ADR: bisulfan lung, dark pigmentation of skin

Thio-TEPA

aziridine

used topically by instillation into bladder and for skin cancers

Altretamine

triazene

oral only

ADR: peripheral neuropathy, CNS changes

cimetidine inhibits metabolism

dacarbazine

metabolized to an active methylator

IV only

Temozolomide

PRODRUG of MTIC

oral only

Procarbazine

oxidized to an azo compound which generates an active methylating species

oral only

ADR: sensitizes tissue to radiation (memory), CNS sedative effects, MAOI, increased BP with tyramine and other sympathomimetics, Antabuse effect with ETOH

Platin MOA

only the cis derivative can form a cross link with DNA

reacts with N-7 of guanine and adenine, primarily with neighboring guanines on the same strand

cause a bending of the DNA duplex towards the major groove, which inhibits DNA synthesis (DNA polymerase rides in the major groove)

Cisplatin

platin

hydrate form is active

IV only

dose limiting toxicities: nephrotoxicity, peripheral neuropathy, ototoxicity

Amifostine

reduces neuro and nephrotoxicity of platins

PRODRUG

ADR: short term hypotension during administration and 5-15 mins after infusion, N/V

Carboplatin

PRODRUG of cisplatin (must undergo hydrolysis)

IV only

ADR: less N/V, less nephrotoxic, BMS (DL)

Oxaliplatin

shown to be effective in patients no longer responding to 1st gen platins

less overall toxicity (neuropathy and pulmonary fibrosis rare)

Imatinib

MOA: inhibitor of protein tyrosine kinase leading to inhibition of proliferation and induction of apoptosis in Bcr-Abl positive cells , also inhibits receptor TK for platelet derived growth factor, stem cell factor, and c-kit

ADR: edema

Hydroxyurea

MOA: inhibitor of ribonucleotide reductase (RNR), holds cells in G1 phase

Methotrexate

MOA: inhibits DHF reductase, which prevents reduction of DHF to THF; less 5,10 methylene THF is available at each cycle due to the consumption of THF during the conversion of dUMP to TMP; inhibits TMP production; inhibits IMP; S phase specific

analog of folic acid

ADR: nephrotoxicity at high doses, renal excretion is inhibited by NSAIDs, ASA and penicillins reduce excretion

Leucovorin

reverses toxic effects of methotrexate

converts to the various forms of one carbon THF that the cell needs

5- fluorouracil (5FU)

MOA: uridine phosphylase converts it to 5FUMP then RNR converts it to 5FdUMP which is an inhibitor of thymidylate synthase; leads to a decreased production of TMP which causes DNA synthesis to shutdown

can be used topically for skin cancers

Leucorvin can enhance toxicity

Floxuridine

MOA: decreased production of TMP

needs to be phosphorylated for activity

more active and toxic

used inter arterially

Capecitabine

PRODRUG of 5FU

undergoes enzymatic ester hydrolysis, followed by deamination by cytidine deaminase to give uridine derivative, which is then converted to 5FU by thymidine phosphorylase

Cytarabine (Ara-C)

arabinose analog of cytidine, must be activated to the triphosphate, deoxycytidine kinase does the first phosphorylation; inhibits chain elongation

Azacitibine

activated to the triphosphate and incorporated into RNA and DNA, inhibits methylation of DNA (important in gene expression)

given SQ

ADR: neurotoxicity and nephrotoxicity

Gemcitabine

difluoro deoxycytidine analog; S phase specific

IV only

MOA: biochemically activated by kinase to its di/triphosphate; diphosphate inhibits RNR,; triphosphate competes with dCTP for incorporation into DNA, which causes chain termination

ADR: Renal toxicity, fever, rash

Cladribine

converted to the triphosphate which allosterically inhibits RNR, also incorporated into DNA causing pausing and termination of strand elongation, resistant to adenosine deaminase

ADR: fever and chillsP

Pentostatin

inhibitor of adenosine deaminase, causes inhibition of RNR

ADR: altered taste, fever and chills, myalgias

Fludarabine

converted to triphosphate, incorporated into DNA and RNA, causes chain termination, also inhibits RNR, resistant to adenosine deaminase

ADR: fever/chills, infections, blindness, coma

Mercaptopurine (6-MP)

thio analog of hypoxanthine, converted to 6-thio inosine monophosphate by HGPRT, acts as inosine analog, inhibits committed step in purine synthesis and conversion of IMP to AMP & GMP

can use allopurinol to decrease dose of 6-MP

Azathioprine

PRODRUG of 6-MP

Thioguanine (6-TG)

converted to 6-thioguanosine monophosphate by HGPRT; inhibits de novo purine synthesis, AMP & GMP synthesis, and incorporated into DNA/RNA

anti-tumor antibiotics

interacts with DNA via intercalation (insertions between base pairs), which inhibits enzymes of DNA/RNA synthesis or induces strand breaks in DNA

Bleomycin

MOA: DNA binding region intercalates into DNA and metal binding region chelates iron, iron is oxidized and oxygen is reduced to make ROS that cause DNA strand breaks

IV and direct instillation into bladder

ADR: pigmentation of skin and nail beds, erythema and ulceration of elbows, knuckles and other pressure points, cell memory, pulmonary toxicity (DL)

Actinomycin D

MOA: intercalates between adjacent guanosine-cytosine base pairs of DNA, cyclic peptides extend into minor groove; inhibits transcription of DNA; can cause single strand breaks in DNA via free radical generation or inhibition of topoisomerase II

IV only

ADR: sore throat and mouth ulcers

reduce dose in renal and hepatic impairment

anthracyclines

MOA: intercalates into DNA with no base pair preference, inhibits topoisomerase II, chelates iron which can form a complex with DNA

ADR: cardiotoxicity (EKG changes and cardiomyopathy)

cardiomyopathy is a cumulative dose dependent effect

Dexrazoxane

competes for iron and reduces the incidence of CHF

increases the total cumulative dose allowed

Doxorubicin

anthracycline

ADR: CHF (DL), red discoloration of urine, skin can become red and peeling can occur, sensitizes tissue to radiation (memory)

Daunorubicin

ADR: CHF (DL)< red urine, mouth ulcers, alopecia, recall reaction

Epirubicin

low incidence of CHF if <550 mg/m cumulative dose

structurally similar to doxorubicin

Idarubicin

very potent

metabolite is cardiotoxic

Valrubicin

instillation into bladder for those who have failed first line therapy for bladder carcinoma

ADR: red urine for 24 hrs after instillation

mitoxantrone

reduced free radical production

less cardiotoxic and N/V

MOA: intercalates into DNA and inhibits topoisomerase II

ADR: mouth ulcers, blue discoloration of urine, fingernails, whites of eyes, and around injection site

pilamycin

MOA: intercalates into DNA with preference for G-C base pairs and interferes with RNA synthesis

ADR: thrombocytopenia, bleeding disorders due to decreased calcium, mouth ulcers, and CNS depression

mitomycin

MOA: reduction of the quinone followed by loss of the methoxy group activates the compound, functions as alkylating agent and causes cross linking of DNA to induce single strand breaks

ADR: pulmonary fibrosis

vinca alkaloids

MOA: bind to free tubular dimer protein and inhibit its assembly into microtubules; spindles are destroyed and cells arrest in metaphase, leaves them more susceptible to S phase agentsV

Vincristine

ADR: CNS toxicity, peripheral neuropathy (DL), autonomic neuropathy (constipation, urinary retention, orthostatic hypotension)

Vinblastine

ADR: neurotoxicity less common and less severe, BMS (DL)

Vindesine

ADR: neurotoxicity (less severe than vincristine)

Vinorelbine

ADR: neurotoxicity (more severe than vinblastine, less than vincristine)

epipodophyllotoxins

MOA: formation of a complex with DNA and topoisomerase II results in double stranded breaks in DNA; cells in S and G2 phase are most sensivive

Etoposide

oral or IV

ADR: mouth ulcers, diarrhea, alopecia, allergic reaction

Etoposide phosphate

more water soluble

rapidly converted to etoposide in plasma

Teniposide

IV only

Taxanes

promotes assembly of microtubules, binds to tubules and inhibits disassembly, results in bundles of microtubules and random assemblages of microtubules with no apparent function

drugs that inhibit DNA and block block progression of cell through S-phase to M-phase antagonize the effects

Paclitaxel

ADR: peripheral neuropathy, hypersensitivity, hypotension, bradycardia (may be due to cremophor EL)

Docetaxel

ADR: same as pacitaxel

drug interaction with 3A inhibitors

Cabazitaxel

BBW: neutropenia and severe hypersensitivity

strong 3A4 inhibitor

Camptothecin derivatives (-tecan)

inhibits topoisomerase I, inhibits reformation of the DNA strand, eventually leads to double stranded breaks

Topotecan

IV only

Irinotecan

PRODRUG, activated by esterase

IV only

ADR: diarrhea

aminoglutethimide

inhibits conversion of cholesterol to pregnenolone which decreases gluco/mineralocorticoids, estrogens, and androgens

ADR: rash, drowsiness, hypothyroid

Mitotane

toxic to adrenal cortex cell (MOA Unknown)

ADR: diarrhea, CNS depression

Flutamide, Nilutamide, Bicalutamide

amide derivatives that block the testosterone receptor

ADR: gynecomastia, impotence, diarrhea, pulmonary fibrosis

Anastrozole, Letrozole

inhibit aromatase

ADR: headache, hot flashes, loss of strength and energy

Exemestane

irreversible aromatase inactivator

ADR: similar to other aromatase inhibitor

Cyclosporine

MOA: reversible inhibition of immuno competent lymphocytes in G0 and G1, T-cells are preferentially inhibited, inhibits lymphokines and release of IL2

ADR: anaphylaxis after IV admin (Cremophor EL), nephrotoxicity and hepatotoxicity

Tacrolimus (FK-506)

MOA: binds to intracellular protein (FKBP-12), inhibits calcineurin phosphatase which prevents dephosphorylation and translocation of nuclear factors which normally initiates gene transcription of lymphokines

ADR: post transplant diabetes, neurotoxicity, nephrotoxicity, anaphylaxis (cremophor EL), HTN, diarrhea

BBW: increase infection and chance of lymphoma

should not be used with cyclosporin, 1 day washout

Sirolimus

MOA: binds to FKBP-12 and to a key regulatory kinase, suppressing cytokine driven T-cell proliferation, inhibiting the progression from G1 to S phase

ADR: nephrotoxic, HTN, diarrhea, HA, tremor

BBW: increased risk of infection and lymphomas and other malignancies (skin)

Temsirolimus

MOA: binds to FKBP-12 which inhibits nTOR that controls cell division resulting in G1 growth arrest; prevents phosphorylation of two key proteins in the PI2/AKT pathway and reduces levels of hypoxia

ADR: hypersensitivity (polysorbate 80), increased BG levels, increased infections, interstitial lung disease

Pimecrolimus

topical cream for atopic dermatitis

MOA: binds to FKBP-12 and inhibits calcineurin to inhibit T cell activation; also prevents release of inflammatory substances from mast cells

Mycophenolate mofentil

PRODRUG of mycophenolic acid

used in combination with cyclosporine and corticosteroids

MOA: uncompetitive reversible inhibitor of IMPDH which converts IMP to XMP; inhibits production of GMP, suppresses antibody formation in B-cells, and inhibits recruitment of leukocytes