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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