I. Alkylating I. Alkylating Agents & Agents & Related Related

CompoundsCompounds

Alkylating agents used in cancer chemotherapy include a diverse group of chemicals

that have in common the capacity to contribute alkyl

groups to DNA (alkylation of DNA)

Alkylating agents are CCNS, proliferating cells are more

sensitive to the drugs

Alkylating agents are used in combination with other

agents to treat lymphatic and solid tumors

Alkylating agents are mutagenic, and carcinogenic (may lead to acute leukemia)

Resistance may occur during treatment with alkylating

agents

Major classes of Major classes of alkylating agentsalkylating agents

Nitrogen mustards Nitrosoureas

CyclophosphamideMechlorethamine

ChlorambucilMelphalan

Carmustine LomustineStreptozoci

n

Alkyl sulfonates

Busulfan

Related agents

Platinium analogues; Cisplatin, Carboplatin, OxaliplatinThiazines; Dacarbazine

MOAMOA of alkylating of alkylating agentagent

Intrastrand

Cross

Alkylating agentsAlkylating agents form covalent bonds between form covalent bonds between

alkyl groups of the drug and N-7 of alkyl groups of the drug and N-7 of guanine bases of DNAguanine bases of DNA

Intrastrand Intrastrand and and crosscross linkinglinkingof DNA of DNA

interferes with transcription, interferes with transcription,

stops replication of DNA stops replication of DNA

(Inhibit cell division)(Inhibit cell division) DNA is unable to DNA is unable to

replicatereplicate

1.Nitrogen 1.Nitrogen mustardmustardss

Nitrogen mustards are Nitrogen mustards are related to the 'mustard related to the 'mustard

gas' used during the first gas' used during the first world war and caused world war and caused

severe myelosuppressionsevere myelosuppression

CyclophosphamideCyclophosphamide Cyclophosphamide is the most commonly Cyclophosphamide is the most commonly

used alkylating agent used alkylating agent Cyclophosphamide is a Cyclophosphamide is a prodrugprodrug, well , well

absorbed orally absorbed orally It is usually given orally or by IV or IMIt is usually given orally or by IV or IM Activated by the liver microsomal Activated by the liver microsomal

cytochrome P 450 to the cytotoxic cytochrome P 450 to the cytotoxic metabolites; metabolites; phosphoramide mustard and phosphoramide mustard and acrolein acrolein

Reaction of phosphoramide mustard with Reaction of phosphoramide mustard with DNA is the DNA is the cytotoxic stepcytotoxic step

Causes myelosuppression (especially Causes myelosuppression (especially lymphocytes)lymphocytes)

Cyclophosphamide MetabolismCyclophosphamide Metabolism

Clinical uses of Clinical uses of Cyclophoshamide Cyclophoshamide

Ovarian cancer

Lung cancer

Breast Cancer (CMF) Cyclophoshamide,

methotrexate & fluorouracil

Hodgkin disease & other lymphomas

Other clinical uses of Other clinical uses of CyclophoshamideCyclophoshamide

Cyclophosphamide is a potent Cyclophosphamide is a potent immuno-suppressantimmuno-suppressant drug used drug used in: in:

(a) control of organ rejection (a) control of organ rejection after after

transplantationtransplantation (b) disorders associated with (b) disorders associated with

altered altered immune reactivity such as immune reactivity such as intractable intractable rheumatoid arthritisrheumatoid arthritis

Common adverse effects Common adverse effects of Cyclophosphamideof Cyclophosphamide

Amenorrhea, testicular atrophy & sterility.

Bone marrow depression

Alopecia, Nausea & Vomiting, diarrhea

Carcinogenesis may appear years after therapy (acute leukemia)

Adverse effects of Adverse effects of CyclophosphamideCyclophosphamide

Characteristic toxicity: Hemorrhagic cystitis

It is due to toxic metabolite “acrolein” in urine fibrosis of the bladder

Prevented by: Proper hydration + IV of mercaptoethane sulfonate “MESNA”

Sterile hemorrhagic cystitis due to Sterile hemorrhagic cystitis due to chemical irritation produced by chemical irritation produced by reactive metabolites of reactive metabolites of cyclophosphamide cyclophosphamide (acrolein) (acrolein) in urine in urine

can be ameliorated by increasing fluid can be ameliorated by increasing fluid intake and administering compounds intake and administering compounds that are that are sulphydryl donorssulphydryl donors, e.g. NA-2-, e.g. NA-2-mercaptoethane sulfonate (MESNA) mercaptoethane sulfonate (MESNA)

MESNA neutralizes the toxin acrolein, MESNA neutralizes the toxin acrolein, forming a non-toxic compound.forming a non-toxic compound.

ChlorambucilChlorambucilAn alkylating agent used An alkylating agent used

in treatment of in treatment of chronic chronic lymphocytic leukemia lymphocytic leukemia

Chlorambucil causes bone Chlorambucil causes bone marrow depression and marrow depression and

GITGIT upsetupset Chlorambucil is Chlorambucil is

mutagenicmutagenic

MelphalanMelphalan It is used to treat It is used to treat multiple myeloma multiple myeloma

and ovarian cancerand ovarian cancer Oral or IVOral or IV Common side effects include:Common side effects include: N, V and oral ulcerationN, V and oral ulceration BM suppression, includingBM suppression, including

Decreased WBC count causing Decreased WBC count causing increased risk of infectionincreased risk of infection

Decreased platelet count causing Decreased platelet count causing increased risk of bleedingincreased risk of bleeding

2-Alkyl sulfonates2-Alkyl sulfonates

BusulfanBusulfan

BusulfanBusulfan The main pharmacological action The main pharmacological action

of busulfan is myelosuppression, of busulfan is myelosuppression, in low dosage in low dosage granulocytesgranulocytes

and platelets and platelets in higher dosage red cellsin higher dosage red cells

Therapeutic uses:Therapeutic uses: Busulfan is the drug of choice in Busulfan is the drug of choice in

chronic granulocytic leukemiachronic granulocytic leukemia

BusulfanBusulfan

Adverse effects: Myelosuppression N, V and diarrheaCarcinogenic

Characteristic toxicity:1. Pulmonary fibrosis 2. Skin pigmentation 3. Adrenal insufficiency

3-Nitrosoureas 3-Nitrosoureas include a nitroso (R-NO) group and include a nitroso (R-NO) group and

a urea.a urea.

Carmustine Carmustine

LomustineLomustine

StreptozocinStreptozocin

Carmustine and Carmustine and LomustineLomustine

Use: Treatment of tumors of brain & meninges

High lipid solubilitycross the BBB

They have a severe

cumulative depressive effect on the BM that

starts 3-6 weeks after initiation of

treatment

StreptozocinStreptozocin

Use: Treatment of insulinoma

Toxic to the β cells of islets of

Langerhans

Used in medical research to Used in medical research to produce an animal model for produce an animal model for Type 1 diabetes in large dose Type 1 diabetes in large dose as well as Type 2 diabetes as well as Type 2 diabetes with multiple low doses.with multiple low doses.

Platinum Platinum complexescomplexes

CisplatinCisplatin

CarboplatinCarboplatin

OxaliplatinOxaliplatin

CisplatinCisplatin Cisplatin is a water-soluble complex Cisplatin is a water-soluble complex

containing a containing a central platinum atom central platinum atom alkylating agents : causing crosslinking alkylating agents : causing crosslinking

of DNA, which triggers of DNA, which triggers apoptosis(programmed cell death).apoptosis(programmed cell death).

It is a It is a nephrotoxic, nephrotoxic, renal function is renal function is assessed assessed by creatinine clearanceby creatinine clearance and and strict regimens of hydration and strict regimens of hydration and diuresis must be initiated diuresis must be initiated

CisplatinCisplatin is one of the most emetogenic is one of the most emetogenic chemotherapy agentschemotherapy agents

effective against testicular cancereffective against testicular cancer

CISPLATICISPLATINN

NH3

NH3

Pt

Cl

Cl

Cisdiaminedichloroplatinum II, CDDP

Mechanism of antitumour Mechanism of antitumour activityactivity

Chloride atomsChloride atoms are replaced by water forming a are replaced by water forming a positively charged hydrated species that form positively charged hydrated species that form strong covalent bonds with electron rich atoms in strong covalent bonds with electron rich atoms in nucleic acids and proteins resulting in:nucleic acids and proteins resulting in:

DNA interstrand cross-linksDNA interstrand cross-links DNA intrastrand cross-linksDNA intrastrand cross-links DNA-protein cross-linkDNA-protein cross-link Monofunctional and Bifunctional Monofunctional and Bifunctional

alkylationalkylation

CISPLATICISPLATINN

NH3

NH3

Pt

Cl

Cl

Cisdiaminedichloroplatinum II, CDDP

H20+

H20+

CDDP-INDUCED ORGAN TOXICITYCDDP-INDUCED ORGAN TOXICITY

* *

* Neurotoxicity* Neurotoxicity

* Cardiomyopathy* Cardiomyopathy

* Hepatotoxicity* Hepatotoxicity

Nephrotoxicity

CLINICAL TREATMENT OF CDDP-CLINICAL TREATMENT OF CDDP-INDUCED NEPHROTOXICITYINDUCED NEPHROTOXICITY

1- 1- Intensive hydration and diuresis.Intensive hydration and diuresis.2- Dosing according to kidney function.2- Dosing according to kidney function.

- BUN- BUN- Serum creatinine- Serum creatinine- Creatinine clearance- Creatinine clearance

3- Avoiding concomitant use of other3- Avoiding concomitant use of other nephrotoxic drugs.nephrotoxic drugs.4- Employing New Analogues4- Employing New Analogues

- Carboplatin- Carboplatin- Oxaliplatin- Oxaliplatin

CisplatinCisplatin

1. 1. Severe N/V Severe N/V

2. Dose-related 2. Dose-related

nephrotoxicity nephrotoxicity (Rx (Rx

hydration, hydration, mannitol)mannitol)

3. Neurotoxic; 3. Neurotoxic; peripheralperipheral

neuritis neuritis +Ototoxicity +Ototoxicity

4. Less 4. Less MyelotoxicMyelotoxic

Broad-spectrum agents, fighting solid tumors: breast, ovarian, testicular, lung,

bladder cancersCarboplatinCarboplatin

1. Much less N/V1. Much less N/V

2. Much less 2. Much less nephrotoxicitynephrotoxicity

3. Less risk of 3. Less risk of peripheral peripheral neuropathy , neuropathy , ototoxicityototoxicity

4. It is more myelotoxic dose-limited toxicity blood cells decrease blood cells decrease dramatically, dramatically, sometimes as low as sometimes as low as 10% of its usual 10% of its usual production levels. production levels.

A new member of this class A new member of this class with better pharmacological with better pharmacological profile profile

Used in the treatment of Used in the treatment of colorectal cancer colorectal cancer with other with other anticancer drugs. anticancer drugs.

Oxaliplatin

DacarbazineDacarbazine Belong to Thiazines Is a prodrug, activated in the liver,

and the resulting compound is cleaved in

the target cell to release an alkylating derivative Treatment of melanomas

Common adverse effects: Severe nausea & vomitingMyelotoxicityHepatotoxicity

Resistance to Resistance to alkylating agentsalkylating agents

Increased DNA repair Decreased permeability of

the drug Increased conjugation with

thiols (trapping agents)

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