Pharmacology Review Sheets: Cancer chemotherapy drugs, p.

1
Drug Selection
Drugs partially effective when used alone, at optimal dose and schedule
Drug selected from a class should not have any common toxicities w/other drugs in combination therapy
Give combinations at regular intervals, preferably as narrow as possible (to allow for recovery of most sensitive tissues
bone marrow, GI tract, etc.)
Advantages of selecting drugs in this way:
- Provide maximal cell kill within the range of toxicity tolerated by the host for each drug
- Provide a broader range of coverage at the outset for possible resistant cell lines in the heterogenous tumor
population
- Prevent or slow the development of new resistant cell lines.
Chromatin function inhibitors (Mitotic spindle poisons): Vinca alkaloids
Common properties
Mechanism of action: Combines with tubulin, resulting in disassembly of microtubules; specific for phases G2/M in the
cell cycle
Resistance:
- Membrane P-glycoprotein pumps drug out (Note: P-glycoprotein is present in most cells; resistant cells simply
have an upregulation of P-glycoprotein)
- Mutation to tubulin so it doesnt bind the drug
Pharmacokinetics:
- Administration: IV
- Distribution: Distributes well to heart, kidney, lung, liver. Does NOT distribute to CSF. Passes the placental
barrier.
- Excretion: Feces (biliary route)
Common Adverse Reactions/Drug Interactions:
- Nausea, vomiting, diarrhea (NVD)
- Alopecia
- Severe constipation
- Interaction: Itracanazole admin time to neuromuscular problems.

Drug

Uses

Adverse Effects

Vincristine (VX) Acute lymphocytic leukemia (ALL)

Peripheral neuropathy
Hodgkin's & non-Hodgkin's lymphoma
Inappropriate ADH secretion (avoid vigorous hydration
in patients receiving high doses of vincristine)
Wilms tumor
Ewing's soft tissue sarcoma
Vinblastine (VBL) Disseminated non-seminomatous testicular cancer
Myelosuppression granulocytopenia
Choriocarcinoma
Hodgkin's lymphoma.
Vinorelbine (VRB)(Not listed)
Myelosuppression granulocytopenia
Chromatin function inhibitors (Mitotic spindle poisons): Taxanes
Drug

Mechs of Action/Resistance
Pharmacokinetics
Uses
Adverse
Effects
Paclitaxel
Mechanism of action: Promotes and stabilizes the Admin: IV infusion, but w./special solvent b/c drug
Solid tumors
Severe neutropenia (Rx w/filgrastim C-GSF)
microtubule assembly; chromosome desegregation
is insoluble in water
3
Epithelial ovarian cancer - Don't give to pts w/neutrophil count < 1500/mm
won't take place apoptosis results.
- Give immunosuppressants (dexamethasone,
- Non-small cell
lung cancer Peripheral neuropathy ( risk in diabetics)
Specific for the G2/M phases of the cell cycle.
diphenylamine) + cimetidine/ranitidine beforehand
(w/cisplatin or carboplatin)
Alopecia
Resistance:
Distribution: Extensively bound to serum proteins

Cardiovascular toxicities
- Membrane P-glycoprotein pumps drug out
but does NOT enter the brain
Onycholysis
- Mutation to tubulin so it doesnt bind the drug Metabolism: CYP2C8, then CYP3A4
Excretion: Feces

Docetaxel
Mechanism of action: Same as w/paclitaxel but with
Admin: Same as with paclitaxel, but
(Same as paclitaxel)
Severe neutropenia (Rx w/filgrastim C-GSF)
affinity (thus activity)
- Only dexamethasone needs to be given first!
3
- Don't give to pts w/neutrophil count < 1500/mm
Resistance: Same as w/paclitaxel
Distribution: Same as paclitaxel but may penetrate
Peripheral neuropathy ( risk in diabetics)
cells better
Alopecia
Metabolism: CYP3A4
Fluid retention
Excretion: Feces
Erythema

Pharmacology Review Sheets: Cancer chemotherapy drugs, p.2

Chromatin function inhibitors: Antibiotics
Drug/Class Mechs of Action/Resistance
Pharmacokinetics
Uses
Adverse
Effects
Dactinomycin
Mechanism of action:
Administration: IV
Gestational
choriocarcinoma Hypersensitivity: anaphylactic reactions
(aka Actinomycin D)
- Inhibit DNA-dependent RNA polymerase
Distribution: Well-distributed, but does NOT
Wilms tumor (children)
Stomatitis and ulceration of oral cavity and GI tract
by intercalating between DNA strands and
penetrate CSF
Rhabdomyosarcoma
Pancytopenia (dose-limiting)
blocking RNA chain elongation (Low conc)
Duration of action: Long t
Ewings sarcoma
- Requires daily monitoring
- Inhibition of DNA synthesis (High conc)
Metabolism: Minimal
Colors urine red (warn patients about this)
- Cytotoxic to cells in any phase of the cell
Elimination: Urine and feces
cycle, including those in stationary phase.
Resistance:
- Membrane P-glycoprotein pumps drug out
- Some evidence of changes in topoisomerase II.
DoxorubicinMechanism of action:
Administration:
Doxorubicin:

Cardiotoxicity due to hydroxy radical formation

Daunorubicin
- Intercalates between base pairs
- IV for doxorubicin, daunorubicin
- ALL
- Dose-related, cumulative, non-reversible
(Anthracyclines) - Inhibition of polymerase activity
- Idarubicin can be given orally
Hodgkins lymphoma
- Rx by dexrasone, which is metabolized to EDTA,
- Inhibits topoisomerase II activity; can cause single
Distribution:
- Non-Hodgkins
lymphoma
a metal chelator. It risks anemia though!
or double-strand breaks in DNA
- Highest levels in heart, lung, kidney, liver
- Breast cancer
Bone marrow depression can be severe

- Generation of hydroxyl free radicals

- Doesnt penetrate CSF
- Liver cancer
Hyperpigmentation
- Alterations in cell membrane fxn alters transport
- Penetrates placenta
- Neuroblastoma
Alopecia
Resistance:
Metabolism: Aldo-reductases, to cytotoxic products
Daunorubicin:
Stomatitis
Increased glutathione & glutathione
Excretion: Predominantly biliary
- AML
Mutagenicity/carcinogenicity
peroxidase activity
- Kaposis sarcoma
- Membrane P-glycoprotein pumps drug out
- Decreased topoisomerase II activity.
- DNA repair
Bleomycin
Mechanism of action: Forms a ternary complex with
Administration: IV, IM, subcutaneous or
intrapleural Hodgkins & non-Hodgkins Pulmonary toxicity dose-related, age-related
Fe2+, O2, and DNA forming superoxide and
Distribution: High levels in skin, lung, kidneys,
lymphomas
Mucocutaneous reactions unusual erythema,
hydroxy radicals which fragment DNA
peritoneum, lymphatics. Low levels in BM
Squamous
cell carcinomas
peeling and hyperpigmentation.
- Cells accumulate in the G2 phase
Metabolism: Hydrolase (high levels in BM, low Testicular
carcinoma Anaphylactoid-like reactions
Resistance:
levels in lung and skin) cleaves drug to less potent
(w/cisplatin and
etoposide) Alopecia
- Hydrolase (present in sarcomas) inactivates drug
metabolite

Note: No myelosuppression
- Increased levels of glutathione
Excretion: Urine
- DNA repair.
- Membrane P-glycoprotein pumps drug out
Etoposide
Mech. of action: Inhibits topoisomerase II, causing
Administration: Oral, IV
Testicular
carcinoma, w/
Myelosuppression - dose-limiting
(podophyllotoxin)
double-strand breaks; may also form free radicals
Distribution:
cisplatin
and bleomycin
AML risk

- Affects G2 phase of the cell cycle

- Well-distributed but doesnt penetrate CSF
Small cell lung
carcinoma Hypotension when injected rapidly
Resistance:
- 97% bound to plasma proteins
w/ cyclophosphamide and
Anaphylactic reactions
- Membrane P-glycoprotein pumps drug out
Metabolism: Glucuronidation, sulfation
doxorubicin
Drug Interactions: Aspirin, phenylbutazone can
- Mutation of topoisomerase II.
Excretion: Urine
displace etoposide from plasma protein binding site
- Mutation of p53 tumor suppressor gene
Topotecan
Mechanism of action: Inhibits topoisomerase I, Administration: IV
Refractory
metastatic ovarian Bone marrow suppression neutropenia
(podophyllotoxin)
causing single-strand breaks
Metabolism: Reversible pH-dependent hydrolysis;
cancer
- Dose-limiting
Resistance: Poss. amplification of P-glycoprotein lactone ring is opened at physiologic pH (7.4) Refractory
small cell lung
- Treat with filgrastim (C-GSF)
or mutation of topoisomerase I
and closed at pH 4
carcinoma
3
Dont use in pts with neutrophils < 1500/mm
Elimination: Urine
Nausea, vomiting,
diarrhea

Pharmacology Review Sheets: Cancer chemotherapy drugs, p.3

Antimetabolites
Drug/Class Mechs of Action/Resistance
Pharmacokinetics
Uses
Adverse Effects
Methotrexate
Mechanism of action: Inhibitor of dihydrofolate Administration: Oral, IV, IM, intrathecal

ALL
Stomatitis
reductase (DHFR), depriving cell of folate
Distribution:
Gestational choriocarcinoma
Alopecia
coenzymes needed to synthesize purines,
- Well-distributed in all body fluids except CSF
Epidermoid cancers of head and neck Thrombocytopenia (BM suppression)
thymidylic acid, and methionine
- 50% bound to plasma proteins
Non-Hodgkins
lymphoma
Megaloblastic anemia
- Requires cycling cells; S phase.
Metabolism: Hydroxylation to less water-soluble Non-metastatic
5
osteosarcoma (high dose - Rx: leucovorin (N -CHO-THFA)
- Enters cell by diffusion; undergoes polyglutamation
metabolite; hydration needed to prevent crystaluria
w/leucovorin rescue)
Crystaluria w/high doses
and is retained in the cell
- Recall intracellular conversion to polyglutamates
Psoriasis
and psoriatic arthritis (low dose)
Contraindicated in pregnancy;
Resistance:
Excretion: Urine (parent drug and metabolites)
abortifacient
Amplification of the DHFR gene
Chronic
low-dose therapy can lead to
- affinity of DHFR for MTX.
hepatic fibrosis (Rx for psoriatic arthritis)
- permeability into neoplastic cells
Seizures, paraplegias, learning disabilities
- formation of MTX polyglutamic polymers
w/intrathecal administration
- levels of thymidylate synthetase

6-mercaptopurine Mechanism of action: Hypoxanthine analog;

Administration: Oral; well absorbed
Remission
maintenance in ALL
Bone marrow suppression leukopenia,

(Purimethol )
once converted to the appropriate nucleotide, it uses
Distribution: Widely distributed, poor distr. to
CSF
thrombocytopenia
Anti-purine
HGPRT to form thioinosinic acid (TIMP), this Metabolism: Extensive in liver; metabolized to
Hepatotoxicity
interferes with the de novo synthesis of purines
thiouric acid (via xanthine oxidae, XO) and
If allopurinol is also being administered,
- Effective S phase (cycling cells, obviously)
methylated products
reduce the dose b/c allopurinol is an
Resistance:
Excretion: Urine
XO inhibitor &
will potentiate its effects
- Inability to be transformed to T (IMP) due to:

Dont give to kids w/Lesch-Nyhan this

- levels of HGPRT (Lesch-Nyhan syndrome)
drug b/c they have a deficiency of
- affinity for 6-MP
HGPRT
- entry into cells
- metabolism to thiouric acid by xanthine oxidase
- Change in affinity of ribosylamine-5P synthase.
6-Thioguanine
Mechanisms of action:
Metabolism: via methylation
Treatment of AML,
w/daunorubicin Allopurinol does NOT potentiate effects
Anti-purine
- Inhibition of purine ring synthesis

Otherwise, similar to 6-MP

(its a purine analog)
- Blocks phosphorylation of GMP to GDP
Fludaribine Mechs of action: Incorporation into DNA, resulting in Administration: IV
CLL (Bcell)
Severe myelosuppression (dose-limiting)
(Unnatural - Termination of chain elongation
Distribution: Not established
Autoimmune hemolytic anemia fatal!!

- RNA synthesis
Metabolism: Usually to nucleotide; intestinal bacteria
Edema
F-adenine)
Works on cycling cells in S phase
can split off the sugar, yielding a toxic metabolite
Pulmonary toxicity
Undergoes dephosphorylation, then
(F-adenine)
Paresthesias, peripheral neuropathy
rephosphorylation intraceullarly, forming Excretion: Urine
Fever, infection
F-ara ATP
High doses:
progressive encephalopathy,
Resistance: Not established (DNA repair suggested)
blindness, death
5-Fluorouracil
Mechanism of action: Inhibition of DNA synthesisAdministration: IV, topical
Solid
tumors: colon, breast, ovary, Severe oral/GI tract ulceration (this is
Anti-pyrimidine - After conversion to its corresponding nucleotide
Distribution: Well-distributed; penetrates ascites
pancreas and stomach
why 5-FU cant be given orally)
(5-FdUMP), the drug competes w/dUMP for
fluid; also penetrates CSF
Superficial basal
cell carcinomas Diarrhea (severe)
thymidylate synthetase
Metabolism: Like uracil (look this up).
(topical admin)
BM suppression leukopenia
- Note: The folate coenzyme N5,10 methylene THFA Excretion: Bile
Cardiotoxicity (arrhythmias, angina,
is needed for 5-FU to be effective (the coenzyme
- Note: 5FdUMP and FUTP have t
heart failure)
forms a ternary complex w/thymidylate synthetase
Erythematous desquamation of the palms
and the substrate). In the case of the drug, this
and
soles (following extended infusion)
ternary complex is stable (not transitional) and the
Acute cerebellar syndrome (nystagmus
nucleotide of

process is halted.
speech, ataxia)
Resistance:
- Inability to make fraudulent deoxynucleotide.
- amount of dUMP via gene amplification
- affinity of thymidylate synthetase for 5-FdUMP

Pharmacology Review Sheets: Cancer chemotherapy drugs, p.4

Antimetabolites, continued

slurred
- Rare, but reversible!

Drug/Class Mechs of Action/Resistance

Pharmacokinetics
Uses
Adverse Effects
Capecitabine
Mechanism of action: Prodrug is converted to Administration/Absorption: Oral; well absorbed
Refractory metastatic breast cancer Severe diarrhea
Anti-pyrimidine cytotoxic 5-FU; w/same mech. of action;
Metabolism: Prodrug is converted in the liver
Erythematous desquam. of palms/soles
however, the action is much more tumor-specific!
to dFCR, which is in turn deaminated to dFUR.
(palmar-plantar erythrodysesthesia)
(Tumors thymidine phosphorylase does this)
The tumor specifically hydrolyzes this to 5-FU.
Use cautiously in patients with hepatic or
Excretion: Products of 5-FU metabolism, in bile
renal impairment
Cytarabine
Mechanism of action: Inhibits DNA polymerase Administration: IV, subcutaneous, intrathecal

Acute non-lymphocytic leukemia (AML) Potent myelosuppression

Anti-pyrimidine - Drug is converted into corresponding nucleotide -Distribution: Well distributed throughout body;
w/daunorubicin and 6-TG
Hepatic dysfunction
an antagonist of dCTP
penetrates poorly into CSF
ALL
Seizures with intrathecal therapy
- Also inhibits reduction of CDP to dCDP
Metabolism: Extensively deaminated to ara-U
CML
(blast phase)
- Affects cycling cells in S phase
Excretion: Urine
Resistance:
- formation of unnatural nucleotide
- affinity of ara-CTP for DNA polymerase.
- levels of dCTP due to CTP synthetase activity
- metabolism to uracil arabinoside (ara-U)
GemcitabineMechanism of action:
Administration: IV
Pancreatic
adenocarcinoma
Myelosuppression
Anti-pyrimidine - Converted intracellularly to dFCDP/dFCTP
Metabolism: Deaminated to dFU (inactive)

Locally advanced and metastatic

Flu-like symptoms

cancer

by nucleoside kinase
Excretion: Urine (parent drug and dFU)
Transient elevation of liver enzymes
- dFCDP inhibits ribonucleotide reductase
Proteinuria (rare)
(which will dCTP)
- dFCTP is incorporated into DNA, which will
inhibit DNA synthesis
Resistance:
- Possible alteration to nucleoside kinase

non-small cell lung

(in combination w/cisplatin)

Alkylating agents
Drug/Class Mechs of Action/Resistance
Pharmacokinetics
Uses
Adverse Effects
Mechlorethamine Mechanisms of action: Cytotoxicity (rapid)
Administration: IV only
Hodgkins
disease in MOPP regimen
Severe vomiting (centrally mediated)
- Alkylation of N7 of guanine results in:
- Note: severe damage occurs if drug extravasates

(Mechlorethamine, Oncovin , Prednisone, Severe BM depression

- Depurination makes nicks in the DNA chain,
Procarbazine)
GI toxicity
making it easier to break
Some solid tumors
Latent viral infections (herpes zoster) may
- Cross-linkages in DNA
appear
Resistance:
- DNA repair
- permeability
Cyclophosphamide
Mechanism of action: Cytotoxicity by cross-linking
Administration: Oral
Malignant lymphomas
Hemorrhagic cystitis (leukopenia)

(Cytoxan , CTX)
DNA and depurination (by "nicking")
Distribution: Variable binding to plasma proteins
Hodgkin's disease
- Treat w/MESNA (2-mercapto ethane

- Must be biotransformed to active form

Metabolism: Liver cyt P-450 initially hydrolyzes Burkitt's
lymphoma
sulfonate) to remove toxic metabolites
- Hydroxylation by liver cyt P-450
Excretion: Urine (parent drug and metabolites)
Multiple
myeloma
secretion of ADH (risks water retention)
- Non-enzymatic breakdown to phosphoramide
AML
so monitor hydration levels
mustard and acrolein (both cytotoxic)
ALL
Females: Amenorrhea, sterility
- Mustard cyclizes to form active compound
Neuroblastoma
Males: Testicular atrophy, infertility
Affects both cycling and resting cells
Ovarian adenocarcinoma
Bone marrow depression (leukopenia)
Resistance:
Retinoblastoma
2 malignancies
years after therapy
- Increased glutathione
Psoriasis
- DNA repair.
Nephrotic syndrome (in children)

Pharmacology Review Sheets: Cancer chemotherapy drugs, p.5

Alkylating agents

Drug/Class Mechs of Action/Resistance

Pharmacokinetics
Uses
Adverse Effects
Chlorambucil
Mechanism of action: Cross-links DNA
Administration: Oral
Drug of
choice for CLL
BM suppression
Distribution: Highly bound to plasma albumin and

Sterility
tissue proteins
Leukemia
Metabolism: Oxidized in liver to phenylacetic acid
mustard (active agent); chlorambucil is a prodrug
Excretion: Urine
Cisplatin
Mechanism of action: Cross-links DNA (G-G, G-A);
Administration: IV in saline solution, preferably
Solid tumors
Renal tubular damage
Also inhibits RNA synthesis
those containing chloride so conversion doesnt
- Metastatic
testicular carcinoma
- Dose-related and cumulative; make sure
- Affects cells in all stages of the cell cycle but
happen in the IV drip
- Metastatic
ovarian carcinoma
renal fxn is normal before next dose
especially those in S
Distribution: Concentrates in liver, kidney, intestine,
- Bladder cancer
- Damage potentiated by aminoglycosides
- Note: Only the CIS- form is active!
and ovary, but does NOT penetrate CSF
Ototoxicity: tinnitus and hearing loss,
Resistance:
Excretion: Urine
especially in
children
- High intracellular glutathione

Marked nausea and vomiting

- DNA repair

Myelosuppression (leukopenia,
thrombocytopenia
Sterility
Peripheral neuropathy
Serum electrolyte
disturbances

(hypocalcemia,
hypomagnesemia,
hypokalemia,
hypophosphatemia)
Carmustine (BCNU)
Mechanism of action: Alkylating mechanism
Administration: Carmustine-IV; Lomustine-Oral
Malignant gliomas (including
Delayed hematopoietic depression
Lomustine (CCNU)
inhibits DNA; requires bioactivation
Distribution: Readily penetrates CSF!!
glioblastoma multiforme)
(may be due to metabolites)
Nitrosoureas
- Note: cytotoxicity only affects non-resting cells
Excretion: Urine
Renal toxicity related to therapy duration
Resistance: Unknown, but DNA repair suggested

CNS toxicity
Streptozotocin
Mechanism of action: Nitrosurea w/cytotoxicity
Insulin-secreting islet
cell carcinoma of BM toxicity (minimal)
specific for -cells of pancreas
pancreas
Antibodies
Antibody Mechs of Action/Resistance
Pharmacokinetics
Uses
Adverse Effects
Rituximab
Mechanism of action: Binds to CD20 on all cells, Admin: Slow infusion at weekly intervals for 4 doses
Refractory CD20+ B-cell non-Hodgkins Fever, chills
then promotes lysis
lymphoma

Severe neutropenia, thrombocytopenia

- Note: This can only be used for a
reported
short time because of development of

Cardiac arrhythmias
antibodies against the drug by the host
Hypotension, bronchospasm and
angioedema: treat
w/diphenhydramine

and bronchodilator
Metastatic

Trastuzumab
Mechanism of action: Selectively binds human
Administration: IV infusion
breast cancer whose tumors
Fever, chills
epidermal growth factor receptor 2 protein (HER2);
Distribution: Blood levels increased if given with
overexpress HER2; when given with Cardiotoxicity CHF, especially if given
the gene coding for it is amplified in 25-30% of paclitaxel (mechanism unknown)
other agents,
time to progression of
w/anthracyclines (doxorubicin,
women with breast cancer (recombinant Ab)
Metabolism/Excretion: Not described
disease was
lengthened by 25%
daunorubicin) or paclitaxel
- Note: This can only be used for a
Leukopenia, anemia
short time because of development of
antibodies against the drug by the host

Pharmacology Review Sheets: Cancer chemotherapy drugs, p.6

Hormones/Hormone Antagonists
Drug

Mechs of Action/Resistance
Pharmacokinetics
Uses
Adverse Effects
Prednisone
Mechanism of action: Lympholytic effects
Administration: Oral
Leukemias
and lymphomas
Ophthalmic: Cataracts, glaucoma
- Prednisolone (a metabolite) reacts w/the cytosolic
Distribution: Binds to plasma albumin and transcortin
GI: ulcers, pancreatitis

glucocorticoid receptor
Metabolism: Undergoes 11--hydroxylation in liver
Hyperglycemia, Cushing-like Sx
- This receptor-glucocorticoid complex is transported
to prednisolone; glucuronidation later on.
Osteoporosis
to the nucleus and interacts w/DNA effects Excretion: Urine (parent drug and metabolites)
Alterations in mood and behavior
Resistance: Not established

Susceptibility to infections
Tamoxifen
Mechanisms of action:
Administration: Oral
Breast cancer
Hot flashes
anti-estrogen
- Competes with estrogen for the estrogen receptor
Metabolism: Undergoes extensive metabolism;
Prophylaxis in women at risk for breast Vaginal bleeding, discharge
- Drug-receptor complex interferes w/DNA binding,
metabolites are glucuronidated
cancer
Endometrial hyperplasia; poss. cancer
thus TGF-(a promoter of tumor cell growth)Excretion: Feces
Hypercalcemia
- Estrogenic-like activity in endometrium and bone
Thromboembolism
Resistance:
- Downregulation of estrogen receptors
- Possible change in affinity
Leuprolide
Mechanism of action: testicular and ovarian
Administration:
Palliative
treatment of advanced Initial stimulation of FSH and LH release
Goserelin
steroidogenesis
- Leuprolide: SC daily or IM depot form
prostate cancer
lead to testosterone levels, resulting in
- LHRH agonists, but w/chronic administration, - Goserelin: Slow release implant
- Tumor flare
pituitary cells are desensitized (they downregulate
Metabolism/Excretion: Not determined
- Hematuria
GnRH receptors) and lead to a in FSH and LH
- Urinary tract obstruction

Resistance: Unknown
w/antiandrogen (i.e. flutamide)

Flutamide
flashes

Mechanisms of action:

- Inhibits uptake of androgen

Gynecomastia
- Inhibits nuclear binding of androgen in target tissue
Hepatotoxicity
Resistance: Unknown

Rx
Impotence, libido
Peripheral edema
Hot

Miscellaneous
Drug

Mechs of Action/Resistance
Pharmacokinetics
Uses
Adverse Effects
Procarbazine
Mechanism of action: Inhibits DNA/RNA synthesis;
Admin: Oral, parental
Hodgkins
disease (part of MOPP) Nausea, vomiting, diarrhea
also cuts DNA
Distribution: Quickly distributes betw. plasma & CSF
Myelosuppression
- May possibly involve free radical oxidation
Metabolism: Oxidation to azo derivative and H2O2;
Psychic disturbances (it inhibits MAO)
- Inhibits monoamine oxidase (MAO)
Excretion: Urine (metabolites and parent drug)
- Warn pt. against eating foods containing
Resistance: Unknown
tyramine
(aged cheeses, etc)
Disulfuram-like
reaction w/alcohol
Mutagenic (nonlymphocytic)
Teratogenic

L-asparaginase
Mechanism of action: Hydrolyzes blood asparagine,
Admin: IV or IM (b/c it is destroyed by gastric
ALL (w/vincristine and prednisone) Hypersensitivity (b/c its a foreign protein)
thus depriving cells of a required AA
enzymes)

clotting factors
Resistance: Inactivation of enzyme by protease Metabolism/Excretion: Undefined
Pancreatitis
Neurotoxicity
Hydroxyurea
Mechanism of action: Inhibits ribonucleotide
Admin/Absorption: Oral; well absorbed

Busulfan-resistant chronic granulocytic

BM suppression (leukopenia):
reductase (thus preventing conversion of
Distribution: Very well, even to CSF
leukemia
- Dose-limiting
ribonucleoside diphosphates to the corresponding
Excretion: Urine
Head and neck
cancer (w/radiotherapy) Megaloblastosis
deoxyribonucleotide diphosphate)
Polycythemia vera
Dermatologic problems (scaling and
Sickle cell anemia (b/c it causes the atrophy of
skin, hyperpigmentation,
body to produce fetal Hb)
nail
damage, erythema) w/chronic therapy
Teratogenic
Pharmacology Review Sheets: Cancer chemotherapy drugs, p.7 By excretion and major side-effects
Renal Excretion
(Dactinomycin minor route)
Bleomycin
Etoposide
Topotecan
Methotrexate
6-mercaptopurine (6-MP)

Gemcitabine
Cyclophosphamide
Chlorambucil
Cisplatin
Prednisone
Procarbazine

Biliary/Fecal Excretion
Vinca alkaloids (vincristine, vinblastine, vinorelbine)
Taxanes (paclitaxel, docetaxel)
Dactinomycin (major route of excretion)
Anthracyclines (doxorubicin, daunorubicin)
5-fluorouraci (5-FU)
Capecitabine

Fludarabine
Cytarabine

Hydroxyurea

Tamoxifen

Bone marrow suppression

Bone marrow suppression, continued
NO bone marrow suppression
Vinblastine
myelosuppression granulocytopenia
Fludaribine
myelosuppression
Vincristine
Vinorelbine
myelosuppression granulocytopenia
5-fluorouracil (5-FU)
leukopenia
Bleomycin
Paclitaxel
neutropenia
Cytarabine
myelosuppression
Capecitabine
Docetaxel
neutropenia
Gemcitabine
myelosuppression
Prednisone
Dactinomycin
pancytopenia
Mechlorethamine
severe BM suppression
Tamoxifen
Doxorubicin
myelosuppression
Cyclophosphamide
leukopenia
Leuprolide
Daunorubicin
myelosuppression
Chlorambucil
BM suppression
Goserelin
Etoposide
myelosuppression
Cisplatin
leukopenia, thrombocytopenia
Flutamide
Topotecan
neutropenia
Rituximab
neutropenia, thrombocytopenia
L-asparaginase
Methotrexate
thrombocytopenia
Trastuzumab
leukopenia, anemia
6-mercaptopurine (6-MP)
leukopenia, thrombocytopenia
Procarbazine
myelosuppression
6-thioguanine (6-TG)
leukopenia, thrombocytopenia
Hydroxyurea
leukopenia
Cardiovascular toxicities
Pulmonary toxicities
Contraindicated in pregnancy
Paclitaxel
Bleomycin
Methotrexate (abortifacient)

Hepatotoxicity
6-mercaptopurine (6-MP)

Peripheral neuropathy
Vincristine

Doxorubicin

Fludaribine
Procarbazine (teratogenic)

Cytarabine (hepatic dysfunction)

Daunorubicin
Hydroxyurea (teratogenic)
5-Fluorouracil (5-FU)
Trastuzumab
Rituximab (cardiac arrhythmias)

Docetaxel
Fludaribine
Cisplatin

Alterations of sexual function

malignancies
Cyclophosphamide
Females: Amenorrhea, sterility
Doxorubicin
Males: Testicular atrophy, sterility
Chlorambucil
Sterility
AML
Cisplatin
Sterility
Cyclophosphamide
Tamoxifen
Signs of menopause (hot flashes)
Tamoxifen
Poss. endometrial cancer
Leuprolide, Goserelin
Impotence, libido
Procarbazine
Non-lymphocytic leukemia
Flutamide
Hot flashes, gynecomastia
Other adverse side-effects

Paclitaxel

Mutagenic/Secondary

Daunorubicin
Etoposide

Other adverse side effects, continued

Vincristine, cyclophosphamide
Inappropriate ADH secretion
tubular damage (nephrotoxicity)
Docetaxel
Fluid retention
Cisplatin
Dactinomycin
Colors urine red
Cisplatin
disturbances (hypocalcemia, hypomagnesemia,
Methotrexate
Megaloblastic anemia (b/c of folate deficiency)
hypokalemia, hypophosphatemia)

Cisplatin

Renal

Ototoxicity
Electrolyte

 Methotrexate
Crystaluria (at high doses)
Prednisone
glaucoma
6-mercaptopurine (6-MP)
Potentiated by allopurinol (cp. 6-TG, which is not)
Prednisone
Hyperglycemia
Fludarabine
Autoimmune hemolytic anemia (fatal!!)
Tamoxifen
Hypercalcemia
5-Fluorouracil (5-FU)
Acute cerebellar syndrome (reversible)
Procarbazine
Psychic disturbances (MAO inhibitor)
5-Fluorouracil, capecitabine
Palmar-plantar erythrodysesthesia
Procarbazine
Disulfuram-like effect
(erythematous desquamation of palms/soles)
Methotrexate, cytarabine
Seizures w/intrathecal administration
Mechlorethamine
Latent viral infections (zoster) reappear
Cyclophosphamide
Hemorrhagic cystitis

Cataracts,

Pharmacology Review Sheets: Immunosuppressive Drugs, p.1

Glucocorticoids
Drug

Mechs of Action/Resistance
Pharmacokinetics
Uses
Adverse Effects
Prednisone
Mech of action: Non-specific immune suppression
Administration: Oral
Leukemias and lymphomas
Ophthalmic: Cataracts, glaucoma

Prednisolone

- Peripheral lymphocytopenia; T-cells > B-cells Distribution: Binds to plasma albumin and transcortin
GI: ulcers, pancreatitis
- Suppresses production of IL-1, IL-2
Metabolism: Undergoes 11--hydroxylation in liver
Hyperglycemia
- Inhibits T-lymphocyte proliferation
to prednisolone; glucuronidation later on.
Osteoporosis
Intracellular mechanism:
Excretion: Urine (parent drug and metabolites)
Alterations in mood and behavior
- Prednisolone reacts w/cyt. glucocort. receptor
Susceptibility to infections
- Receptor-glucocorticoid complex is transported
to the nucleus, interacting w/DNA effects
Resistance: Not established

Antimetabolites
Drug

Mechs of Action/Resistance
Pharmacokinetics
Uses
Adverse Effects
Azathioprine
Mechanism of action: Interferes in de novo synthesis
Administration: Oral, IV
Adjunct to
prevention of rejection in Bone marrow suppression leukopenia,
Pro-drug of 6-MP
of purine (non-specific); prodrug is reduced to 6-MP Metabolism: Rapidly metabolized to either
thiouric
renal transplantation
thrombocytopenia
and then to TIMP
acid or methylated derivatives in liver and RBCs Management of
severe rheumatoid Hepatotoxicity
- Lymphocytes most affected b/c of dependence on
Excretion: Urine
arthritis which
doesnt respond to other Reduce dose if allopurinol is also being
de novo purine synthesis; T- & B-cells both affected
medication
administered, b/c it can potentiate effects
Resistance: Similar to that of 6-MP
Nausea,
vomiting
Risk of infection

Mycophenolate Mechanism of action: Interferes w/de novo synthesis

Administration/Absorption: Oral (complete) or IV
Prophylaxis against rejection in kidney, GI: Vomiting, diarrhea, rare GI
mofetil
of purines (non-specific)
Distribution: MPA is 97% bound to serum albumin,
heart transplants in combination with
hemorrhage (3%)
- Prodrug is metabolized to mycophenolic acid
but no displacement reactions have been reported
cyclosporine or glucocorticoids Sepsis, CMV
(MPA), which inhibits inosine monophosphate Metabolism: Liver, glucuronidation
- Can be used to
treat acute rejection
Abdominal pain
dehydrogenase, which catalyzes formation of Excretion: Urine (glucuronide)
refractory
episodes
Leukopenia, thrombocytopenia
guanosine from IMP
Mutagenic, but
less than azathioprine
- Inhibits glycosylation of adhesion molecules

Drug Interactions:
- Inhibits production of Abs, possibly cytokines
Acyclovir/gancyclovir: may compete for
tubular secretion
- Mg2+ and Al3+
antacids oral absorption
- Cholestyramine Rx
blood levels
Antibodies
Antibody Mechs of Action/Resistance
Pharmacokinetics
Uses
Adverse Effects
Antilymphocyte & Mechanism of action: Binds to surface of circulating
Admin: IM, IV (over several hours)
Treatment of allograft rejection during
Foreign proteins can lead to fever, chills,
antithymocyte
T-cells; leads to opsonization/phagocytosis in
Duration of action: t = 3-9 days
acute phase & steroid-resistant rejections
leukopenia, thrombocytopenia, rashes
globulins
liver and spleen

Muromonab-CD3 Mechanisms of action:

Admin: IV, usually following methylprednisone, Prevention of
acute rejection (depletes Anaphylaxis
- Blocks CD3 receptor so CD3 cant bind
diphenhydramine, and acetaminophen to alleviate
Tcells from donor BM before BM
Cytokine release syndrome (first dose):
- Binds T-cells to inhibit T-cell participation in
cytokine release syndrome
transplant)
- Mild flu-like illness to life-threatening
immune response (this will deplete the T-cells)
shock-like reaction; high fever
CNS: seizures,
encephalopathy, cerebral
edema, aseptic
meningitis, headache
CMV infection
Contraindicated in
patients w/seizure
history,
uncompensated heart failure,
pregnant or breast
feeding
Daclizumab Mechanism of action: Blocks IL-2 receptor
Duration of action: Basiliximab > Daclizumab
No adverse reactionsyet
Basiliximab
Do not seem to cause
Ab formation
Pharmacology Review Sheets: Immunosuppressive Drugs, p.2
Signal Induction Inhibitors

Drug

Mechs of Action/Resistance
Pharmacokinetics
Uses
Adverse Effects
Cyclosporine
Mechanism of action: Specific inhibition of
Admin: Oral (by capsules and microemulsion)

Prevention of rejection after kidney, Nephrotoxicity (reversible w/dose )

T lymphocytes
Absorp: Microemulsion absorbed more completely
heart, liver
transplantation (also
Hepatotoxicity (reversible w/dose )
- Cyclosporine enters cell, binds to cyclophilin; Distribution: Varies among individuals; check
used for
pancreas)
Lymphoma (reversible w/dose )
- This complex interacts w/calcineurin, Ca2+ and blood levels
- Always given with:
Infection (esp. CMV)
calmodulin, inhibiting the dephosphorylation of
- 50% taken up by RBC; 4-9% by lymphocytes
Glucocorticoids + azathioprine, or
- Do NOT reduce dose; makes it worse!
NFATc; this interrupts the formation of IL-2
- 90% of plasma fraction bound to proteins
Mycophenolate mofetil
Others: Seizures, Hirsutism, Gingival
(b/c genes arent induced)
(primarily lipoproteins)
Severe rheumatoid
arthritis or
hyperplasia, HTN, tremor
- IL-2 promotion of T-cell clonal expansion
Metabolism: CYP3A isozyme
psoriasis
that doesnt respond to Drug Interactions:
- 30 metabolites identified
usual therapies

in cyclosporine concentrations:
Excretion: Bile (mostly metabolites)
- Ca2+
channel blockers: diltiazem,
nicardipine,
verapamil
- Antifungals:
fluconazole, itraconazole,
ketoconazole.
- Antibiotics:
erythromycin,
clarithromycin
- Glucocorticoids:
methylprednisolone

- Others: allopurinol,
bromocriptine,
danazol,
metocopramide
Foods: Grapefruit
juice.

in cyclosporine

concentrations:
- Antibiotics:
nafcillin, rifampin
- Anticonvulsants:
carbamazepine,
phenobarbital and
phenytoin.
- Other drugs:
octreotide, ticlopidine
Potentiation of renal
dysfunction:
- Antibiotics:
gentamicin, tobramycin,
vancomycin,
tri/sulfa
- Antineoplastics:
melphalan
- Antifungals:
amphotericin B,
ketoconazole.
- Antiinflammatories:
diclofenac,
naproxen, sulindac
- GI agents:
cimetidine, ranitidine

Immunosuppresants: tacrolimus
Tacrolimus (FK506)
Mechanism of action: Similar to cyclosporine but Admin/Absorption: Oral, IV; best abs. in fasted
state Approved for liver & kidney transplants, Hypersensitivity
100 times more potent
- Fat absorption
but have been used for other
organs
Neurotoxicity (tremor, headache, seizures,
- Binds to a distinct cyclophilin, FKBP-12
Distribution: Levels variable; highly bound to RBCs,
Used to switch from cyclosporine in
coma, delirium) at high doses
( FK binding protein) which binds to calcineurin,
plasma albumin, a1-acid glycoprotein
cases where a renal transplant is failing,
Nephrotoxicity (high doses)
Ca2+ and calmodulin to result in IL-2
Metabolism: CYP3A. Mostly metabolized.
and
cyclosporine may be involved Hyperkalemia
Excretion: Urine
Hyperglycemia
insulin-dependent DM
Hypertension
Infections
Lymphoma
Drug Interactions:
Same as cyclosporine
Sirolimus
Metabolism of action: Interference w/G1 phase
Administration: Oral (fasting state)
Prevention
of rejection in patients w/ High blood chol., hypertriglyceridemia
(rapamycin)
progression in lymphoid and other cells
Absorption: Food interferes w/absorption.
renal transplants (w/cyclosporine and HTN
- Binds to FKBP-12, but inhibits mTOR (a kinase)
Metabolism: CYP3A isozyme
corticosteroids)
Rash, acne
Excretion: Urine
Anemia,
thrombocytopenia
Hypokalemia
Joint pain

 Drug interactions:
Same as cyclosporine
and tacrolimus.
Pharmacology Review Sheets: Immunosuppressive Drugs, p.3
Renal Excretion
Prednisone
Prednisolone
Azathioprine
Mycophenolate mofetil
Tacrolimus
Sirolimus

Biliary/Fecal Excretion
Cyclosporine

Bone marrow suppression

Mutagenic
Contraindicated in
pregnancy
Azathioprine
leukopenia, thrombocytopenia
Azathioprine
Muromonab-CD3
Mycophenolate mofetil leukopenia, thrombocytopenia
Mycophenolate mofetil (< than azathioprine)
Antilymphocyte and
leukopenia, thrombocytopenia
Cyclosporine (lymphomas, reversible)
antithymocyte globulins
Tacrolimus (lymphomas)
Sirolimus
anemia, thrombocytopenia
Nephrotoxicity
Sirolimus)
Cyclosporine (reversible)
Tacrolimus

Hepatotoxicity

Neurotoxicity

Cyclosporine (reversible)

Tacrolimus

Infections (Exception:

Prednisone
Prednisolone
Azathioprine
Mycophenolate mofetil CMV, HSV
Muromonab-CD3
CMV
Cyclosporine
CMV
Tacrolimus