Chapter 21 alkylating agents,platins,antimetabolites

ALKYLATING AGENTS
PLATINS
ANTIMETABOLITES -

ALKYLATING AGENTS
• cell cycle–phase nonspecific.
• DNA and RNA and proteins are alkylated (N-7 position of guanine)
the O6 group of guanine is alkylated by nitrosoureas.
• Alkylation abnormal nucleotide sequences, miscoding of messenger
RNA, cross-linked DNA strands that cannot replicate, breakage of DNA
strandsdamage to the transcription and translation of genetic
material.
• cross-linking of DNA strands & breaks in DNA. not able to complete
the replication cyclecytotoxicity.
• Tumor resistance  ↑capacity of cells to repair nucleic acid damage and
to inactivate the drugs by conjugation with glutathione.

Altretamine
Indication.- Recurrent ca ovary
Pharmacology
a. M/A- unknown.
b. Metabolism. Rapidly demethylated and hydroxylated in the liver by the
microsomal P450 system. Excreted in urine and hepatobiliary tract as
metabolites
Toxicity
a. Dose limiting. Nausea and vomiting,
b. Common.
• Neurotoxicity (25%), hallucinations,hypoesthesia, hyperreflexia, motor
weakness, confusion,lethargy,including paresthesias, agitation,
coma;depression,
• myelosuppression (mild)
• Nausea , vomiting
c. Occasional.
• Abnormal LFTs, flulike syndrome; abdominal cramps, diarrhea
d. Rare.
• Alopecia, skin rashes, cystitis

Bendamustine
Indications.CLL, low-grade B-cell NHL that has progressed within 6
mths of t/t with a rituximab-containing regimen
Pharmacology. Bendamustine is a bifunctional mechlorethamine
derivative containing a purine-like benzimidazole ring. About 90% of
the drug is excreted in the feces.
Toxicity
a. Dose limiting. -Hematosuppression
b. Common.
• Nausea, vomiting, diarrhea, fever, fatigue, headache, stomatitis, rash,
infusion reactions (consider administering an
antihistamine,acetaminophen, prophylactically)
c. Occasional. Anaphylactic reactions, severe skin reactions, acute renal
failure; peripheral edema, dizziness; myelodysplasia; dysgeusia

Busulfan
Indications. Part of conditioning regimen for BMT, CML palliation
Pharmacology. Acts directly; catabolized to inactive products that are excreted
in the urine.
Toxicity
a. Dose limiting. Reversible and irreversible myelosuppression with slow
recovery
b. Common. Mild GI upset, sterility
c. Occasional. Skin hyperpigmentation,alopecia, rash,gynecomastia, cataracts,
LFT abnormalities; seizures
d. Rare. Pulmonary fibrosis (“busulfan lung”), retroperitoneal fibrosis,
endocardial fibrosis; addisonian-like asthenia (without biochemical evidence
of adrenal insufficiency); hypotension, impotence, hemorrhagic cystitis,
secondary neoplasms

Chlorambucil
Indications. CLL, Waldenström macroglobulinemia, lymphomas
Pharmacology. It acts directly; spontaneously hydrolyzed to inactive
and active products ; also is extensively metabolized by the hepatic
P450 microsomal system. The drug and metabolic products are
excreted in urine.
Toxicity. Least toxic alkylating agent
a. Dose limiting. Myelosuppression
b. Occasional. GI upset , mild LFT alter, sterility, rash
c. Rare. Rash, alopecia, fever; cachexia, pulmonary fibrosis, neurologic
or ocular toxicity, cystitis; acute leukemia

Cyclophosphamide
Indications.HL, lymphocytic lymphoma, mixed cell–type lymphoma, histiocytic lymphoma, Burkitt
lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of
ovary, retinoblastoma, breast carcinoma, conditioning regimen for BMT
Pharmacology. drug is inactive activation by liver P450 system acrolein and an alkylating
metabolite (e.g., phosphoramide mustard). Active and inactive metabolites are excreted in the
urine.
Toxicity
a. Dose limiting
(1) Myelosuppression.
(2)hemorrhagic cystitis-
o prevented by maintaining a high UOP.
o more common and can be severe when massive doses are used (e.g.,BMT); under these circumstances, the
use of mesna can be preventative.
o UB fibrosis with telangiectasia of the mucosa can occur without episodes of cystitis.
o Bladder carcinoma.
b. Side effects
(1) Common. Alopecia, stomatitis, aspermia, amenorrhea; headache
Nausea and vomiting.
(2) Occasional. Skin or fingernail hyperpigmentation; metallic taste during injection; sneezing or a
cold sensation in the nose after injection; abnormal LFTs, dizziness; allergy, fever
(3) Rare. Transient SIADH, hypothyroidism, cataracts,jaundice,pulmonary fibrosis; cardiac necrosis
and acute myopericarditis; secondary neoplasms

Dacarbazine [dimethyl-triazeno-imidazole-carboxamide (DTIC, DIC)
Indications. HL,MM, sarcomas, Neuroblastoma
Pharmacology
a. Mechanisms. Dacarbazine acts as a purine analog and inhibits DNA
synthesis; it is an alkylating agent and it interacts with SH groups.
b. Metabolism. liveroxidative N methylation by CYP 450activation
Excreted in urine predominantly, minor HB & pulmonary excretion
Toxicity
b. Common. Nausea and vomiting (often severe), anorexia; pain along
the injection site
c. Occasional. Alopecia, facial flushing, photosensitivity, abnormal LFTs.
Flulike syndrome
d. Rare. Diarrhea, stomatitis; cerebral dysfunction; hepatic necrosis;
azotemia; anaphylaxis

Ifosfamide
Indications. Lymphomas, sarcomas, relapsed testicular tumors, and
various carcinomas
Pharmacology
a. M/A.- produces phosphotriesters as the predominant rexn products. The t/t of
intact cell nuclei may also result in the formation of DNA–DNA cross-links.
b. Metabolism. hepatic activation acrolein and its alkylating metabolite.
Acrolein is highly toxic to urothelial mucosa.
The chloroacetaldehyde neurotoxic effects, particularly in patients with renal
dysfunction.
Drug and metabolites are excreted in urine.

Toxicity
a. Dose limiting.
Myelosuppression,
hemorrhagic cystitis,
encephalopathy
b. Common. Alopecia; anorexia, constipation, nausea, and vomiting;
amenorrhea, oligospermia, and infertility
c. Neurotoxicity
d. Occasional. Salivation, stomatitis, diarrhea; urticaria,
hyperpigmentation, nail ridging; abnormal LFTs, phlebitis, fever;
hypotension, hypertension, hypokalemia; renal tubular acidosis (at
high doses); SIADH
e. Rare. Coma; renal tubular acidosis, or Fanconi-like syndrome

MESNA
• Inj- 100 mg /ml
• Tablet- 400 mg
• Prevention of ifosfamide HC
240 mg/m2 IV over 15 min before & 4 & 8 hrs after
240 mg/m2 IV 15 min before & 480 mg/m2 of mesna tab 2 & 6 hrs
after
For cyclophosphamide-20% when injected, 4 & 8 hrs after

Melphalan
Indications. MM , BMT
Pharmacology
a. M/A.- A phenylalanine derivative of nitrogen mustard, an alkylating
agent
b. Metabolism. Acts directly. Melphalan is excreted in the urine (about
30%) as unchanged drug and metabolites, remainder in feces.
Toxicity
b. Occasional. Anorexia, nausea, vomiting, mucositis, sterility
c. Rare. Alopecia, pruritus, rash, hypersensitivity; secondary
malignancies (acute leukemia); pulmonary fibrosis, vasculitis, cataracts

Nitrogen mustard (mechlorethamine)
Indication. HL; T-cell lymphoma
Pharmacology
a. M/A -alkylating agents
b. Metabolism. In water or body fluids, mechlorethamine undergoes rapid
chemical transformation ,drug is no longer present in active form a few
minutes after administration. Metabolites are mostly excreted in urine.
Toxicity
b. Common. Severe nausea and vomiting; skin necrosis if extravasated;
burning at IV injection site and facial flushing; metallic taste; discoloration of
the infused vein; abnormal LFTs.
c. Occasional. Alopecia, sterility, diarrhea, thrombophlebitis, gynecomastia
d. Rare. Neurotoxicity (including hearing loss), angioedema, 2nd cancers

Carmustine [BCNU, bischlorethyl nitrosourea (BiCNU)]
Indications. Brain tumors, myeloma, HL & NHL. In high doses for BMT.
In the form of implantable wafers: GBM
Pharmacology
a. M/A. Forms interstrand cross-links in DNA preventing DNA replication and
transcription.
b. Metabolism. Highly lipid-soluble drug that enters the brain. Rapid spontaneous
decomposition to active and inert product. Most of the intact drug and metabolic
products are excreted in urine.
Toxicity
a. Dose limiting. Myelosuppression ,aggravated by concurrent RT.
b. Common. Nausea and vomiting. Local pain during injection.
c. Occasional. Stomatitis, esophagitis, diarrhea, LFT abnormalities; alopecia, facial
flushing, brown discoloration of skin; interstitial lung disease with pulmonary
fibrosis ,dizziness, optic neuritis, ataxia, organic brain syndrome; renal insufficiency
d. Rare. 2nd cancer
Lomustine [CCNU, cyclohexyl chlorethyl nitrosourea]
Indications. Brain tumors & HL

Procarbazine
Indications. HL
Pharmacology
a. M/A- cessation of protein synthesis. Direct DNA damage
b. Metabolism. Hepatic metabolism and activation. Readily enters the CSF.
Toxicity
b. Common. Nausea and vomiting; flulike syndrome; sensitizes tissues to radiation;
amenorrhea and azoospermia, sterility
c. Occasional. Dermatitis, hyperpigmentation, photosensitivity; stomatitis, dysphagia,
diarrhea; hypotension, tachycardia; urinary frequency, hematuria; gynecomastia
d. Neurologic. disorders of consciousness or mild peripheral neuropathies (10%) ,sedation,
depression, agitation, psychosis, decreased deep tendon reflexes, paresthesias, myalgias, and
ataxia.
e. Rare. Xerostomia, retinal hemorrhage, photophobia, papilledema; hypersensitivity
pneumonitis, 2nd cancers

Streptozocin (streptozotocin)
Indications. Islet cell cancer of the pancreas, carcinoid tumors
Pharmacology
a. M/A. Alkylating agent.
A cell cycle–nonspecific nitrosourea analog.
Inhibits DNA synthesis and the DNA repair enzyme, guanine-O6-methyltransferase; affects
pyrimidine nucleotide metabolism and inhibits enzymes involved in gluconeogenesis.
Selectively targets pancreatic β cells, presumably due to the glucose moiety on the molecule.
b.Metabolism. Hepatic metabolism to active metabolites and has a short plasma half-life (<1
hour). Crosses the BBB. Excreted in urine as metabolites and unchanged drug
Toxicity
a. Dose limiting. Nephrotoxicity proteinuria ,glycosuria, aminoaciduria, proximal
RTA, nephrogenic DI, and renal failure
b. Common. Nausea and vomiting, myelosuppression, hypoglycemia after infusion,
hypoglycemia or hyperglycemia
c. Occasional. Diarrhea, abdominal cramps, LFT abnormalities
d. Rare. CNS toxicity, fever, 2ND cancer.

Temozolomide
Indications. Brain tumors; metastatic melanoma
Pharmacology. similar to dacarbazine
a. M/A. Activated to MTIC by nonenzymatic hydrolysis in tumors.
Inhibits DNA, RNA, and protein synthesis but does not cross-link DNA
strands.
b. Metabolism. Renal excretion. Lipophilic  crosses the BBB.
Toxicity
b. Common. nausea and vomiting, diarrhea, headache, fatigue
c. Occasional. Photosensitivity, myalgias, fever
d. Rare. Prolonged cytopenia, myelodysplastic syndrome (MDS)

Thiotepa (triethylenethiophosphoramide)
Indications. Intracavitary for malignant effusions, intravesicular for urinary bladder, and
intrathecal use for meningeal metastasis; severe thrombocytosis. Also can be used for breast
and ovarian cancers and for HSCT
Pharmacology. Ethylenimine analog, chemically related to nitrogen mustard
a. M/A. Alkylates the N-7 position of guanine, which severs the linkage between the purine
base and the sugar and liberates alkylated guanines.
b. Metabolism. Rapidly decomposed in plasma and excreted in urine. Extensively metabolized
by the hepatic P450 microsomal system to active and inactive metabolites
Toxicity
b. Common (for intravesicular administration). Chemical cystitis, abdominal pain, hematuria,
dysuria, frequency, urgency, ureteral obstruction; nausea and vomiting 6 hours after
treatment
c. Occasional. GI upset, abnormal LFTs, hypersensitivity
d. Rare. Alopecia, fever, angioedema, secondary malignancies

Trabectedin
Indications. LS or LMS after an anthracycline containing regimen
Pharmacology
a. M/A. binds guanine residues in the minor groove of DNAadductsaffects binding of transcription
factors and DNA repair.
b. Metabolism. It is metabolized in the liver, and only negligible amount is excreted in urine. The drug is
delivered as a 24-hour continuous infusion.
Toxicity
a. Dose limiting.
Rhabdomyolysis (monitor the level of CPK before each dose),
severe and fatal cardiomyopathy (ECG f/u),
severe neutropenia (40%), febrile neutropenia (5%)
b. Common. Elevation of liver enzymes, thrombocytopenia, anemia, nausea, fatigue, vomiting,
constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache
c. Rare. Liver failure, peripheral neuropathy

PLATINS-
M/A---
• Enters the cells by diffusion and
covalently binds to DNA N-7
position of guanine and adenine.
• Reacts with two different sites on
DNA to produce cross-links, either
intrastrand (>90%) or interstrand
(<5%).
• Formation of DNA adducts results
in inhibition of DNA synthesis and
function as well as inhibition of
transcription
• not cell cycle specific.
M/RESISTANCE---
• alterations in cellular transport.
• Increased inactivation by
glutathione and related enzymes.
• Increased DNA repair enzymes
activity
• Deficiency in mismatch repair
(MMR) enzymes

CISPLATIN
• INDICATIONS
• Testicular cancer
• Ovarian cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Small cell and non-small cell lung cancer
• Non-Hodgkin’s lymphoma
• Trophoblastic neoplasms

DOSAGE RANGE
• Ovarian cancer - 75mg/m2 IV on day 1 every 21 days as part of the cisplatin / paclitaxel regimen,
and 100mg/m2 on day 1 every 21 days as part of cisplatin / cyclophosphamide regimen.
• Testicular cancer - 20 mg/m2 IV on days 1-5 every 21 days as part of the BEP regimen.
• Bladder cancer : administered as a single agent at a dose of 50-70 mg/m2 IV per cycle repeated
every 4 weeks
• Non - small cell lung cancer : 60-100 mg/m2 IV on day 1 every 21 days as part of the cisplatin /
etoposide or cisplatin / gemcitabine regimens.
• Head and neck cancer : 20 mg/m2/day IV continuous infusion * 4 days.

Toxicity
a. Dose limiting
1) renal insufficiency- 5% with adequate hydration 25%-45% without
2) Peripheral sensory neuropathy
>200 mg/m2 and can become dose limiting when the cumulative cisplatin dose exceeds 400
mg/m2.
Symptoms may progress after treatment is discontinued and include loss of proprioception and
vibratory senses, hyporeflexia. Symptoms may resolve slowly after many months.
3) Ototoxicity-
tinnitus and high-frequency hearing loss (5%)
>100 mg/m2 by rapid infusion or high cumulative doses.
b. Common. Severe nausea and vomiting; preventative antiemetic regimens are required.
↓K+↓Mg++
mild myelosuppression alopecia;
azoospermia, sterility, impotence.
c. Occasional. Alopecia, loss of taste, vein irritation, transiently abnormal LFTs, SIADH, hypophosphatemia,
myalgia, fever; optic neuritis
d. Rare. Altered color perception and reversible focal encephalopathy that often causes cortical blindness.
Raynaud phenomenon, bradycardia, bundle-branch block, congestive heart failure; anaphylaxis, tetany

Prevention of nephrotoxicity
• Pre-hydration
• Cisplatin dose < 50mg/m2 : N/Saline in 1L × 1 hour. If another drug is being given
in the regimen e.g. etoposide then this would be used as prehydration i.e.
etoposide in 1L N/Saline.
• Cisplatin dose 50-75mg/m2 : N/Saline + KCl 20mmol/L in 1L × 1hr+ 100mls 10%
mannitol (or equivalent)
• Cisplatin dose > 75mg/m2 < 100mg/m2 : N/Saline + KCl 20mmol/L in 1L × 1hr +
200mls 10% mannitol (or equivalent)
• Cisplatin should not be given if UOP is < 100ml/hr.
• If urine output is insufficient, give 500ml N/Saline × 30mins. Consider giving
further mannitol. Do not administer cisplatin until urine output is > 100ml/hr.

• Post-hydration
• Cisplatin dose < 50mg/m2 : no post-hydration, recommend oral
intake of 8 glasses of water.
• Cisplatin dose > 50mg/m2 < 75mg/m2 : N/Saline + KCl 20mmol/L +
MgSO4 10mmol/L in 1L × 1 hr.
• Cisplatin dose > 75mg/m2 < 100mg/m2 : N/Saline + KCl 20mmol/L +
MgSO4 10mmol/L in 1L × 1 hr x 2. Monitor BP as required

contraindications
• History of hypersensitivity to cisplatin or other platinum containing
compounds.
• Pre-existing renal impairment, myelosuppressed patients or patients with
hearing impairment.
• Pregnancy, breastfeeding

CARBOPLATIN
• INDICATIONS
• Ovarian cancer
• Germ cell tumors
• Head and neck cancer
• Small cell and non small cell
lung cancer
• Bladder cancer
• Relapsed and refractory acute
leukemia
• Endometrial cancer
Pharmacology
a. M/A. Heavy metal alkylating-
like agent with mechanisms very
similar to cisplatin, but with
different toxicity profile
b. Metabolism. Plasma half-life of
only 2 to 3 hours. Excreted in
urine as unchanged drug (70%)
and metabolites

Dosage range
• Dose of carboplatin is usually calculated to a target area under the curve (AUC) based
on the glomerular filtration rate (GFR).
• Calvert formula is used to calculate dose –
Total dose (mg) = ( target AUC ) x ( GFR + 25 )
• Note: dose is in mg, not mg/m2
• Target AUC is usually between 5 and 7 mg/mL/min for previously untreated patients. In
previously treated patients , lower AUCs (between 4 and 6 mg/mL/min) are
recommended .
• AUCs >7 are not associated with improved response rates.

• CrCl + 25 =AUC
• FOR WEEKLY DOSING ~2 AUC
• FOR 3 WEEKLY DOSING 5-6 AUC
OUR SET UP PRACTICE

Toxicity
a. Dose limiting. Myelosuppressionespecially thrombocytopenia.
b. Common. Nausea, vomiting, myalgias, weakness, and nephrotoxicity pain at injection
site; cation electrolyte imbalance
c. Occasional. Reversible abnormal LFTs, azotemia; peripheral neuropathy (5%), visual
disturbance; hypersensitivity reactions; amenorrhea, azoospermia, impotence, and
sterility
d. Rare. Alopecia, rash, flulike syndrome, hematuria, hyperamylasemia; hearing loss,
optic neuritis; alopecia
C/I—
• History of hypersensitivity to cisplatin or other platinum containing compounds.
• Severe bone marrow depression or significant bleeding
• Pregnancy category D; breastfeeding should be avoided

OXALIPLATIN
• It is available as 50 mg/ 100 mg
vials.
• Reconstituted by using 10 ml
(for 50 mg vial) and 20 ml (for
100 mg vial) of Water or 5%
Dextrose injection.
• It is further diluted in 250-500
ml of 5% Dextrose injection.
• Reconstitution of final dilution
must never be performed with
NaCl solution or other chloride
containing solutions.
Indications. Colorectal,
pancreatic, and gastric cancers
Pharmacology
a. Mechanisms. Binds covalently
to DNA -intrastrand and
interstrand cross-links.
b. Metabolism. Undergoes
extensive nonenzymatic
conversion to its active cytotoxic
species; >50% -kidneys. Only 2% -
feces.

INDICATIONS
• Metastatic colorectal cancer : FDA - approved in combination with
infusional 5-FU/LV in patients with advanced, metastatic disease.
• Early stage colon cancer : FDA - approved as adjuvant therapy in
combination with infusional 5 –FU/LV in patients with stage III colon
cancer and also effective in patients with high risk stage II disease.
• Metastatic pancreatic cancer
• Metastatic gastric cancer and gastroesophageal cancer
• DOSAGE--
• Recommended dose is 85 mg/m2 IV over 2 hours, on an every 2 weeks
schedule.
• Can also administer 100-130 mg/m2 IV on an every 3 - weeks schedule.

Oxaliplatin
Toxicity
a. Dose limiting
(1) Acute dysesthesias in the hands, feet, perioral area, or throat develop
within hrs or up to 2 days after dosing and may be precipitated or exacerbated by
exposure to cold -usually resolves within 2 weeks-ameliorated by prolonging the
infusion to 6 hrs.
(2) Persistent peripheral sensory neuropathy usually characterized by
paresthesias, dysesthesias, and hypesthesia, including deficits in proprioception,
which is usually reversible within 4 mths of discontinuing oxaliplatin.
b. Common. Anorexia, nausea, vomiting, constipation, diarrhea,
• abdominal pain; fever, fatigue; mild to moderate myelosuppression; mild to moderate LFT
abnormalities
c. Occasional. Allergic reactions, mild nephrotoxicity, headache, stomatitis, taste alteration;
back pain, arthralgias
d. Rare. Pulmonary fibrosis

contraindications
• Known history of hypersensitivity to oxaliplatin
• Pregnant
• Breast feeding
• Myelosuppression
• Peripheral sensory neuropathy with functional impairment prior to
first course
• Severely impaired renal function

Toxicity profiles of platinum analogs in use
TOXICITY CISPLATIN CARBOPLATIN OXALIPLATIN
MYELOSUPPRESSION
+
NEPHROTOXICITY
+
NEUROTOXICITY
+ +
OTOTOXICITY
+
NAUSEA AND VOMITTING
+ + +

ANTI-METABOLITE CLASSIFIACTION
•ANTIFOLATE
• METHOTRAXATE
• PEMETREXED
• PRALATREXATE
•FLUOROPYRIMIDINES
• 5-FU
• CAPACITABINE
•DEOXYCYTIDINE
ANALOGS
• CYTARABINE
• GEMCITABINE
•PURINE ANALOGS
• 6-MP
• 6-TG
• FLUDARABINE
• CLADRIBINE
• CLOFARABINE

ANTIMETABOLITES
• General pharmacology of antimetabolites
1. structure resemblance to purine or pyrimidine precursors or because they interfere
with purine or pyrimidine synthesis.
2. Greatest activity in the S phase
3. most effective when cell proliferation is rapid.
Azacitidine
Indication. Myelodysplastic syndromes (MDS)
Pharmacology
a. M/A-cytidine analogincorporated into DNA and RNAinhibiting protein synthesis; also
inhibits pyrimidine synthesis and DNA methylation.
Toxicity
a. Dose limiting. Myelosuppression; nausea and vomiting.
b. Common. Hepatic dysfunction, fatigue, headache, diarrhea, alopecia, fever, injection site
erythema
c. Occasional. Neurotoxicity ,azotemia, arthralgias, hypophosphatemia with myalgia,
stomatitis, phlebitis, rash
d. Rare. Progressive lethargy and coma, renal tubular acidosis, rhabdomyolysis, hypotension

Cladribine
Indications. Hairy cell leukemia
Pharmacology.
a. M/A. An analog of the purine deoxyadenosine.
Inhibits ribonucleotide reductase. Depletes ATP. Induces apoptosis.
Active against both dividing and resting cells
Toxicity. Patients are at increased risk for opportunistic infections.
b. Common. Immunosuppression with decreases in CD4+ and CD8+ cells; nausea,
skin reactions at injection site; fever , chills, flulike syndrome
c. Occasional. Neurotoxicity, hypersensitivity reactions, fatigue
d. Rare. Severe neurotoxicity, pancreatitis

Clofarabine
Indications. Relapsed or refractory ALL
Pharmacology. Purine antimetabolite
Toxicity
a. Dose limiting.
(1) Capillary leak syndrome (CLS)/SIRS –due to cytokine release
(2) Hematosuppression (90%)
(3) Hepatotoxicity and nephrotoxicity
b. Common. Tachycardia, hypotension, flushing; headache, fever, chills, fatigue;
pruritus, rash; nausea, vomiting, diarrhea; abnormal LFTs (80%); increased
creatinine (50%), limb pain
c. Occasional. Hypertension, edema, dyspnea, pleural, or pericardial effusion;
mucositis; myalgia, arthralgia; irritability, somnolence, agitation; cecitis; CLS (4%),
SIRS (2%)
d. Rare. Hepatic venoocclusive disease, Stevens-Johnson syndrome, hallucination

Cytarabine
Indications. Acute leukemia, lymphoma, meningeal involvement with tumor
Pharmacology. An analog of deoxycytidine
a. M/A. Antimetabolite.Intracellular activation ara-CTPinhibits DNA
polymerases; some are incorporated into DNA.
Ara-CTP inhibits ribonucleotide reductase DNA synthesis and function.
b. Metabolism. In patients with renal insufficiencyhigh concentrations of ara-
CTP, which may result in CNS toxicity.
Toxicity
b. Common. Nausea, vomiting, mucositis, diarrhea; conjunctivitis; hydradenitis,
arachnoiditis with intrathecal administration
c. Neurotoxicity (cerebellar ataxia, lethargy, confusion)
d. Occasional. Alopecia, stomatitis, metallic taste, esophagitis, hepatic dysfunction,
pancreatitis, severe GI ulceration; thrombophlebitis; headache; rash, transient skin
erythema without exfoliation.

Decitabine
Indications. MDS
Pharmacology. analogue of 2′-decoxycytidine.
a. M/A- inhibits DNA methyltransferase, causing hypomethylation of
DNA and cellular differentiation or apoptosis.
Toxicity
a. Dose limiting. Hematosuppression
b. Common. Hematosuppression, fatigue, fever; nausea, constipation
(35%), diarrhea; headache, arthralgias, rigors, edema, cough;
hyperglycemia, ↓K+, ↓ Mg++

Fludarabine
Indications. CLL, low-grade lymphomas
Pharmacology. analog of ara-A (arabinofuranosyladenosine).
drug is resistant to adenosine deaminase activity(compare with
cytarabine).
high specificity for lymphoid cells.
It has activity against both dividing and resting cells and induces
apoptosis.
Toxicity
a. Dose limiting. Myelosuppression; AIHA
b. Common. Immunosuppression -risk for opportunistic infections;
mild nausea and vomiting; fever; cough, weakness, arthralgia/myalgias
c. Occasional. Alopecia (mild), abnormal LFTs, tumor lysis syndrome

5-Fluorouracil
A fluoropyrimidine analog
M/A- blocking thymidylate synthetase (TS)interfere with DNA syn
Incorporation of another metabolite (FdUTP) into DNA results in inhibition
of DNA synthesis and function.
It is cell–cycle S-phase specific but acts in other cell cycle phases as well.
5-FU rapidly enters all tissues, including spinal fluid and malignant
effusions.
Toxicity is more common and more severe in patients with
dihydropyrimidine dehydrogenase deficiency.

TOXICITY
a. Dose limiting. Myelosuppression; mucositis; diarrhea
b. Common. Nasal discharge; eye irritation and excessive lacrimation due to
dacryocystitis and lacrimal duct stenosis; dry skin, photosensitivity, and
pigmentation of the infused vein
c. Neurologic. Reversible cerebellar dysfunction, somnolence, confusion, or
seizures occurs in about 1% of patients.
d. Occasional. Esophagitis; hand–foot syndrome; coronary vasospasm;
thrombophlebitis; nausea, vomiting
e. Rare. Alopecia, dermatitis, loss of nails, dark bands on nails; blurred vision,
“black hairy tongue” (hypertrophy of filiform papillae), anaphylaxis, fever

Capecitabine
Indications. breast or colon ca
Pharmacology. Capecitabine is a fluoropyrimidine carbamate that is a systemic
prodrug of 5′-deoxy-5-fluorouridine (5′-DFUR), which is converted in vivo to 5-FU.
M/A & metabolism & toxicity- same as 5-FU.
Toxicity.
a. Dose limiting. Diarrhea (50%), hand–foot syndrome
b. Common. Hand–foot syndrome -15% to 50%; nausea, vomiting,
hematosuppression; fatigue
c. Occasional. Abnormal LFTs, neurotoxicity; cardiac ischemia in patients with a
prior history of coronary artery disease; tear duct stenosis, conjunctivitis,
blepharitis; confusion, cerebellar ataxia

Gemcitabine
Indications. Carcinoma of pancreas, bladder, lung, ovary; STS
Pharmacology. A fluorine-substituted deoxycytidine analog
a. M/A. Cell-phase specific-S phase -blocking the progression of cells
through the G1-S-phase also.
Inhibits ribonucleotide reductase; competes with deoxycytidine
triphosphate (dCTP) for incorporation into DNA
Toxicity
b. Common. Nausea, vomiting, diarrhea, stomatitis; fever with flulike symptoms (40%);
macular or maculopapular rash; transient LFT elevations; mild proteinuria and hematuria
c. Occasional. Hair loss, rash, edema
d. Rare. Hemolytic–uremic syndrome; pulmonary drug toxicity; hypersensitivity reactions;
alopecia

Hydroxyurea
Indications. MPD, refractory ca ovary, sickle cell disease
Pharmacology. An analog of urea
a. M/A. Antimetabolite.
inhibiting nucleotide reductaseinterfere with DNA syn
Inhibits DNA repair and thymidine incorporation into DNA.
Cell cycle S-phase specific but acts in other phases as well
b. Metabolism. Crosses the BBB. Half of the drug is rapidly degraded into
inactive compounds by the liver. Inactive products and unchanged drug (50%)
are excreted in urine.
Toxicity
b. Occasional. Nausea, vomiting, diarrhea; skin rash, facial erythema, hyperpigmentation; azotemia,
proteinuria; transient LFT abnormalities;
c. Rare. Alopecia, mucositis, diarrhea, constipation; neurologic events; pulmonary edema; flulike
syndrome; painful perimalleolar ulcers; possible acute leukemia in myeloproliferative disorders

6-Mercaptopurine
Indication. Acute lymphoblastic leukemia (maintenance therapy)
a. M/A- Purine analog
The parent drug is inactive. Requires intracellular phosphorylation –
HGPRTase
b. Metabolism-by xanthine oxidase.
Allopurinol- XO inhibitortoxicity.
Toxicity
b. Common. Mild nausea, vomiting, anorexia (25%); usually reversible
cholestasis (30%); dry skin, photosensitivity; immunosuppression
c. Rare. Stomatitis, diarrhea, dermatitis, fever, hematuria, BuddChiari–
like syndrome, hepatic necrosis

Methotrexate
Indications. A wide variety of conditions
a.M/A- interfere with DNA syn.
The drug also inhibits RNA and protein
synthesis and prevents cells from entering the S
phase of the cell cycle.
b. Metabolism. Renal dysfunction results in
dangerous blood levels of MTX and possible
further renal damage.

Toxicity. Leucovorin can reverse the immediate cytotoxic effects of
MTX; generally, 1 mg of leucovorin is given for each 1 mg of MTX.
a. Dose limiting. Myelosuppression, stomatitis, renal dysfunction
b. High-dose regimens. Nausea, vomiting, renal tubular necrosis,
cortical blindness
c. Skin erythema, pulmonary fibrosis, transverse myelitis, cerebritis
d. Chronic therapy. Liver cirrhosis; osteoporosis
e. Neurotoxicity. acute aseptic meningitis,subacute encephalopathy and myelopathy. irreversible
leukoencephalopathy
f. Occasional. Nausea, vomiting, dermatitis, photosensitivity, altered pigmentation, furunculosis;
conjunctivitis, photophobia, excessive lacrimation, cataracts; fever, reversible oligospermia, flank pain
g. Rare. Alopecia, MTX pneumonitis

Pemetrexed
Indications. Mesothelioma (with cisplatin) & NSCLC
a. M/A. antifolate analog
activity in the S phase of the cell cycle.
Inhibition of TS & DHFRase.
b. Metabolism- cleared by the kidneys. About 90% of the drug is
excreted unchanged in the urine within 24 hours.
Toxicity.
a. Dose limiting. Myelosuppression.
All patients are given 350 μg/d PO of folic acid and 1,000 mg of vitamin B12 SC
every 3 weeks to reduce drug toxicity.
b. Common. Skin rash (usually as the hand–foot syndrome), mucositis,
nausea, vomiting, diarrhea; mild dyspnea, fatigue; transient elevation
of LFTs
c. Occasional. Myalgia/arthralgia, fever

Pentostatin
Indications. CLL, hairy cell leukemia, and cutaneous T-cell lymphoma
Pharmacology. A fermentation product of Streptomyces antibioticus
a. M/A- Antimetabolite.
Both cell cycle specific and cell cycle nonspecific.
Inhibitor of adenine deaminase., ribonucleotide reductase
b. Metabolism. excreted unchanged in urine.
Toxicity
b. Common. Immunosuppression; mild nausea and vomiting, diarrhea,
altered taste; fatigue, fever; erythematous, papular, vesiculobullous
rashes
c. Occasional. Chills, myalgia, arthralgia; abnormal LFTs;
keratoconjunctivitis, photophobia; cough, renal failure

Pralatrexate
Indications. Relapsed or refractory peripheral T-cell lymphoma
Pharmacology: An antineoplastic folate analog
a. M/A. Competitively inhibits DHFRase and polyglutamylation by the
enzyme folylpolyglutamyl synthetase
b. Metabolism. Approximately 33% of the drug is excreted unchanged
in the urine.
Toxicity
a. Dose limiting. Thrombocytopenia, neutropenia, and mucositis
b. Common. Anorexia, nausea, vomiting, diarrhea, constipation;
fatigue, fever, edema; rash
d. Rare. Hepatitis; pulmonary infiltrates and insufficiency

6-Thioguanine
Indication. AML
a. M/A. Purine analog with cell cycle–specific activity in the S phase.
The drug requires intracellular phosphorylation by HGPRT
The drug is incorporated extensively into DNA, resulting in miscoding
of transcription and DNA replication, and into RNA.
b. Metabolism.
can be given in full doses with allopurinol.
Clearance of the drug is primarily hepatic, but also renal.
Toxicity
b. Common. Stomatitis, diarrhea
c. Occasional. Nausea and vomiting, hepatic dysfunction, hepatic
venoocclusive disease; decreased vibratory sensation, unsteady gait

Chapter 21 alkylating agents,platins,antimetabolites

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Chapter 21 alkylating agents,platins,antimetabolites