Alkylating Agents

Dr.Neenu Thomas1st Yr PG, Dept. Of Radiotherapy

HISTORY• Mechlorethamine-

first alkylating agent-1942

• Analogue of Sulphur mustard gas

• Weapon in first world war-1917

Alkylating Agents

Nitrogen Mustards

CarmustineLomustineStreptozotocin

BusulfanCyclophosphamideIfosfamideMelphalanChlorambucilMechlorethamine

AziridinesAlkyl

Sulfonates

Nitrosoureas Triazenes

DacarbazineTemozolomide

Thio TEPA

Mechanism of DNA alkylation by a reactive nitrogen mustard molecule and formation of

interstrand cross-link

MOA

Monofunctional adducts and 1,2- and 1,3-interstrand and intrastrand cross-links induced

by DNA interactive agents. X = antitumour agent.

MOA

CYCLOPHOSPHAMIDE

• Inactive in parent form • Activated by liver cyt-

p450 to cytotoxic metabolites PM & acrolein

• DNA adduct

MOA

Mechanism of Action

PHARMACOKINETICS• ROA- iv in Dextrose 5% or

NaCl 0.9 %, Oral• Absorption bioavailability

90%• Vol of Dist-0.6L/Kg• Distribution-including brain

& csf,also in milk & saliva• Protein binding- <20%

Cyclophosphamide & Ifosfamide

PHARMACOKINETICS• Metabolism- Prodrug

activation by Cyt-p450 active forms are 4 hydroxycyclophosphamide phosphoramide mustard & acrolein

• Elimination-t1/2- 4-6 hours parent drug & metabolites exclusively in urine

Cyclophosphamide & Ifosfamide

Indications• Breast Cancer• Ovarian Cancer• Sarcoma• NHL• High dose regimen-in bone

marrow transplantation and for other autoimmune disorders

Dosage range• Breast cancer 100mg/m2 po

days 1-14 every 28 days,iv 600mg/m2 every 21 days AC or CMF

• NHL 400-600 mg/m2 iv every 21 days CVP,750mg/m2 every 21 days CHOP

• High dose BMT 60mg/kg iv for 2 days

DRUG INTERACTION • Inhibit Activation of CP

– Antifungal Agents– Allopurinol– Chlorpromazine– Thiotepa

• Enzyme inducers– Steroids– Anticonvulsants

• Cp increase the effect Anticoagulants • Dec. the plasma levels of digoxin• Inc. the risk of doxorubicin induced cardiotoxicity

• Caution in patients with abnl renal fuction

• Encourage fluid intake 2-3l/day

• Empty bladder several times daily

Special consideration

• Myelosuppression- dose limiting mainly leukopenia 7-14 days

• Nausea & vomiting 2-4 hrs• Alopecia 2-3 wks • Amenorrhoea with ovarian failure • Cardiotoxicity• Sec malig AML & bladder cancer• SIADH

Toxicity

TOXICITY

• Hemorrhagic cystitis- Excretion of Acrolein– Rx

• Adequate hydration• Continuous irrigation of bladder with

MESNA (2mercaptoethanesulfonate)• Frequent bladder emptying

– MESNA• Free sulfhydryl• Divided doses every 4 hrs- 60% of

alkylating agents

TOXICITY

IFOSFAMIDE

• ROA- oral or iv • Absorption- bioavailability

100%• Distribution- Widely

distributed• Protein binding 20%• Metabolism in liver • Elimination- 50-70% excreted

in urine • T1/2- 3 -10hrs

PHARMACOKINETICS

Indication • Osteogenic sarcoma • Ewing sarcoma• HL &NHL • Non small cell & small cell lung

cancer• Bladder cancer • Recurrent germ cell tumors

Drug Interaction • Anticonvulsants, cimetidine &

allopurinol increase the metabolism –enhanced toxicity

• Cisplatin increases renal toxicity • Enhances anticoagulant effects

of warfarin

• Caution in patients with abnl renal function

• Uroprotection with mesna & hydration

• Monitor coagulation parameters

Special consideration

Toxicity• Myelosuppression• Bladder toxicity dose limiting • Alopecia >80 %• Amenorrhoea oligospermia

• High dose ifosfamide– Neurotoxicity

• Seizures, altered mental status,CN palsies, coma

• Painful and acute exacerbation of peripheral sensory neuropathies and motor dysfunction of distal extremities

• N-linked Chloroethyl Chloro Acetaldehyde

TOXICITY

OxidationN-Deethylation

Recommendations High risk - S.Cr>1.5mg or S.Albumin <3g/dl or both Multiple day regimens reduce risk Monitor-early signs(irritability,anxiety,hallucinations) Terminate ifosfamide Palliative therapy

Mechlorethamine

• Absorption- not orally bioavailable

• Metabolism- rapid hydrolysis in plasma

• Elimination- >50% in urine

• T ½- 15-20 min

PHARMACOKINETICS

Indication • HL• NHL • Cutaneous T cell lymphoma • Intrapleural intrapericardial

intraperitoneal treatment of metastatic disease

• HL 6 mg/m2 iv D1 &D8 every 28 days MOPP regimen

• Cutaneous 10mg in 60ml sterile water

• Intracavitary use 0.2 0.4 mg/kg

Dosage range

• Sod thiosulfate inactivates

Drug Interaction

• Potent vesicant • Inflammation &

necrosis pvt by instillation of 2.6 % sod thiosulfate solution

Special consideration

Melphalan

Phenylalanine

Mono & Bifunctional DNA Adduct

Mechanism of Action

Melphalan

PHARMACOKINETICS• ROA- Oral & iv• Absorption-oral

absorption poor Bioavail 60% Food Reduces

• Vol of Dist- 0.5L/Kg• Distribution-Protein

binding >50 %Melphalan

PHARMACOKINETICS

• Elimination – via Hydrolysis of chloro ethyl sidechains to mono and dihydroxy forms

• 25-30% in urine • 13-40 min (iv)

Melphalan

• Multiple Myeloma• Ovarian cancer• Myeloablative therapy

– Bone marrow transplant

CLINICAL USE

Melphalan

• Multiple myeloma -9mg/m2 iv D1-D4 every 4 weeks melphalan prednisone regimen

• Transplant 140mg/m2 single agent

Dosage range

DRUG INTERACTION • Cimetidine

– 30% reduction in Melphalan Absorption

– Steroids enhance antitumor activity

– Cyclosporine enhance renal toxicity

Melphalan

Chlorambucil

Aromatic Mustard

PHARMACOKINETICS• ROA- Oral bioavailability

75%• Absorption- Food

Reduces• Distribution-Protein

binding >98 %• CNS Penetration- low

con in CSFChlorambucil

PHARMACOKINETICS• Metabolism-liver cyt

p450 Phenyl acetic acid

• Elimination – 60% of drug metabolites eliminated in urine

• T1/2 1.5-2.5 hrsChlorambucil

• CLL• NHL• HL

Indication

• CLL 0.1 0.2mg/kg Po daily 3-6 wks-initiation

• 2-4mg po daily maintenance

Dosage range

• Anticonvuslants increased formation of toxic metabolites

Drug Interaction

Special consideration• Caution when

combined with allopurinol –drug induced hyperuricemia

• Closely monitor CBCs• Discontinued if

generalised skin rash develops-EM,TEN,SJS

• Myelosupression• Nausea & vomiting • Hyperuricemia• Pulmonary fibrosis & pneumonitis• Skin rash urticaria• Amenorrhoea ,oligospermia • Sec malig

Toxicity

Neurotoxicity–Phenylacetic acid–Oxidative N

dechloroethylation

TOXICITY

Chlorambucil

Thiotepa

Thiotepa

PHARMACOKINETICS• ROA- iv intravesical

Absorption oral incomplete

• Protein binding- <10%• CNS penetration-

CSFcon equivalent to plasma

• Distribution- 0.7L/KgThiotepa

PHARMACOKINETICS

• Metabolism– Thiotepa TEPA– inactivation by CYP2B

• Elimination- 60%in urine – t1/2 < 2hr

Thiotepa

• Breast cancer• Ovarian cancer• HL• NHL

Indication

• 10-20mg/m2 iv every 3-4 weeks

• Intravesical instillation 60mg in 60ml sterile water weekly upto 4 weeks

Dosage range

• Monitor cbc after intravesical adm –bone marrow depression from systemically absorbed drug

• Resuscitation equipment should be available-hypersensitivity

• Caution about the chance of skin changes urticaria, bronzing, flaking

Special consideration

Busulphan

Busulphan

PHARMACOKINETICS• Highly variable

–Age –Circadian variation–Disease type

• ROA- Oral • Absorption- excellent

bioavailabilityBusulphan

PHARMACOKINETICS• CNS Penetration- Enter

Easily• Vol of Dist- 27+/- 11L/m2

• Metabolism- By liver cyt p450

• Elimination-t1/2 2.5hrs• Higher clearance rate in

evening in young– Faster in Children– Less rapidly in leukemic

patients Busulphan

CLINICAL USE

• CML• Myeloablative

treatment- prior to BMT

Busulphan

• CML remission induction 4-8mg/day po

• Maintenance dose 1-3mg/day po

• Transplant 4mg/day iv 4 days

Dosage range

• Pretreatment with Anti convulsants increase rate of elimination by 20%

• Concurrent treatment with CP increases clearance

• Acetaminophen& itraconazole decrease metabolism enhanced toxicity

Busulphan

Drug Interaction

Special consideration• Monitor patients

for pulmonary symptoms

• Ingestion on an empty stomach decrease the risk of nausea

Toxicity• Myelosuppression• Nausea and vomiting >80%• Mucositis• Impotence, male

sterility ,amenorrhoea• Interstitial pulmonary fibrosis

busulfan lung may occur 1-10 yrs after therapy

• Hepatovenoocclusive disease >16mg/day

Nitrosourea

Nitrosourea

Carmustin (BiCNU)

Nitrosourea

By alkylation of DNA and

possibly by carbamoylation

of protein

Mechanism of Action

Nitrosourea

PHARMACOKINETICS• ROA- iv• Absorption- not absorbed

orally• Distribution lipid soluble

drug cross BBB >50%in plasma– Metabolism- Spontaneous

decomposition to chloroethyl carbonium ion

– Isocyanate may also form

Nitrosourea

PHARMACOKINETICS

• Vol of Dist- 3-5 L/kg• Elimination-60-70% in

urine – mostly as metabolites– t1/2 0.4-4.3 h

Nitrosourea

CLINICAL USE• Brain tumour-

GBM,glioma• Multiple

Myeloma• Hodgkins

Lymphoma,NHLNitrosourea

• 200mg/m2 iv every 6 weeks

• Implantable BCNU impregnated wafers at the surgical resection

Dosage range

• Cimetidine & amphotericin B enhances toxicity

• decrease the plasma level of Digoxin & phenytoin

Drug Interaction

• Administer slowly over a period of 1-2 hrs to avoid intense pain & burning

• Pfts should be obtained at baseline

Special consideration

Toxicity• Facial flushing & burning

sensation at the iv site• Hepatotoxicity with elevated

LFT 90% within 1 week ,hepatovenoocclusive d/s 5-20%

• Pulmonary toxicity at cumulative dose >1400

Lomustin (CCNU)

Nitrosourea

• Absorption- completely orally • Distribution- Lipid soluble

drug with broad tissue distribution

• Cross BBB and csf con 15-30 %of plasma levels

• Metabolism- in liver • Elimination- 50% in urine • T1/2- 72 hrs

PHARMACOKINETICS

•Brain tumor•HL•NHL

Indication

130mg/m2 po every 6 weeks

Dosage range

• PFTs monitored periodically

• Administer drug on empty stomach

Special consideration

• Decreased cellular uptake of drug• Decreased expression of drug

activating enzymes of the liver p450 system

• Increased expression of sulfhydryl proteins including gluthathione and asso enzymes

• Increased expression of aldehyde dehydrogenase resulting in enhanced enzymatic detoxification of drug

• Enhanced activity of dna repair enzymes

Mechanism of Resistance

Dacarbazine

Nonclassic alkylating agent

• Methylates nucleic acids and inhibits DNA RNA & protein syn

Mechanism of Action

Mechanism of Resistance• Increased

activity of DNA repair enzymes O6alkyl guanine DNA alkyl transferase (AGAT)

• ROA- iv• Absorption- slow & variable • Distribution- widely

distributed • Protein binding- 20%• Metabolism- in liver to MTIC

AIC• Elimination- 40 -60%

unchanged in urine• t1/2- 5 hrs

PHARMACOKINETICS

• Metastatic malignant melanoma

• HL • Sarcoma• Neuroblastoma

Indication

• HL 375mg/m2 iv D1 D15 every 28 days ABVD

Dosage range

• Heparin lignocaine hydrocortisone incompatible with dacarbazine

• Anticonvulsants decrease the efficacy

Drug Interaction

• Potent vesicant• Use of

aggressive antiemetics

• Avoid sunexposure

Special consideration

Toxicity• Flu like syndrome• CNS toxicity paresthesia

neuropathies, ataxia,seizures

• Photosensitivity• Teratogenic

Temozolomide

TemozolomideSpontaneously releases the cytotoxic species 3-methyl-(triazen-1-yl) imidazole-4-carboxamide(MTIC)

DacarbazineRequires metabolic activation mediated by microsomal enzymes

CH3

• Imidazotetrazine analog• Methylates guanine

residues(N7,O6) in DNA and inhibits DNA,RNA,protein syn

• Cytotoxicity-formation of O6 methyl guanine adducts

Mechanism of Action

Mechanism of Resistance• Increased

activity of DNA repair enzymes O6alkyl guanine DNA alkyl transferase (AGAT)

PHARMACOKINETICS• ROA- Oral,iv• Absorption-

–oral bioavailability 100%

–Food reduces • Peak con- <1 h

Nitrosourea

PHARMACOKINETICS• CNS Penetration- High, CSF

con 30-40% Selective distribution over tumour in brain

• Metabolism- MTIC &AIC• Vol of Dist- 3-5 L/m2

• Elimination-– Majority in urine 40-50%

• t1/2- 1.8hNitrosourea

• 150mg/m2 po daily for 5 days -28 days

• 75mg/m2 po daily for 42 days with RT- GBM

Dosage range

CLINICAL USE

• Glioma• Astrocytoma• Melanoma

Busulphan

DRUG INTERACTION Toxicity increases in prior exposure to nitrosureas

• Moderately emetogenic agent.

• Avoid sun exposure after Rx

• Caution in elderly patients

Special consideration

Toxicity• Myelosupression-Dose

limiting toxicity• Photosensitivity• Teratogenic