Download alkylating_agents_and_related_drugs

I. Alkylating Agents &
Related Compounds
 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 alkylating agents
Nitrogen mustards
Cyclophosphamide
Mechlorethamine
Chlorambucil
Melphalan
Alkyl sulfonates
Busulfan
Nitrosoureas
Carmustine
Lomustine
Streptozocin
Related agents
Platinium analogues; Cisplatin,
Carboplatin, Oxaliplatin
Thiazines; Dacarbazine
MOA of alkylating agent
Cross
Intrastrand
Alkylating agents
form covalent bonds between alkyl
groups of the drug and N-7 of guanine
bases of DNA
Intrastrand and cross linking
of DNA
interferes with transcription,
stops replication of DNA
(Inhibit cell division)
DNA is unable to
replicate
1.Nitrogen mustards
Nitrogen mustards are related
to the 'mustard gas' used
during the first world war and
caused severe
myelosuppression
Cyclophosphamide






Cyclophosphamide is the most commonly used
alkylating agent
Cyclophosphamide is a prodrug, well absorbed
orally
It is usually given orally or by IV or IM
Activated by the liver microsomal cytochrome
P 450 to the cytotoxic metabolites;
phosphoramide mustard and acrolein
Reaction of phosphoramide mustard with DNA is
the cytotoxic step
Causes myelosuppression (especially lymphocytes)
Cyclophosphamide Metabolism
Clinical uses of
Cyclophoshamide
Hodgkin disease &
other lymphomas
Ovarian cancer
Breast Cancer
Lung cancer
(CMF) Cyclophoshamide,
methotrexate & fluorouracil
Other clinical uses of
Cyclophoshamide

Cyclophosphamide is a potent immunosuppressant drug used in:
(a) control of organ rejection after
transplantation
(b) disorders associated with altered
immune reactivity such as
intractable rheumatoid arthritis
Common adverse effects of
Cyclophosphamide
Alopecia, Nausea & Vomiting, diarrhea
Amenorrhea, testicular atrophy & sterility.
Bone marrow depression
Carcinogenesis may appear years after
therapy (acute leukemia)
Adverse effects of
Cyclophosphamide
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
chemical irritation produced by
reactive metabolites of
cyclophosphamide (acrolein) in urine
can be ameliorated by increasing fluid
intake and administering compounds
that are sulphydryl donors, e.g. NA2-mercaptoethane sulfonate (MESNA)
MESNA neutralizes the toxin acrolein,
forming a non-toxic compound.
Chlorambucil
 An
alkylating agent used in
treatment of chronic
lymphocytic leukemia
 Chlorambucil causes bone
marrow depression and
GIT upset
 Chlorambucil is mutagenic
Melphalan





It is used to treat multiple myeloma and
ovarian cancer
Oral or IV
Common side effects include:
N, V and oral ulceration
BM suppression, including
 Decreased WBC count causing increased
risk of infection
 Decreased platelet count causing
increased risk of bleeding
2-Alkyl sulfonates
Busulfan
Busulfan
The main pharmacological action of
busulfan is myelosuppression,
 in low dosage
granulocytes and
platelets
 in higher dosage
red cells
 Therapeutic uses:
 Busulfan is the drug of choice in
chronic granulocytic leukemia

Busulfan
Adverse effects:
 Myelosuppression
 N, V and diarrhea
 Carcinogenic
Characteristic toxicity:
1. Pulmonary fibrosis
2. Skin pigmentation
3. Adrenal insufficiency
3-Nitrosoureas
include a nitroso (R-NO) group and a urea.
Carmustine
Lomustine
Streptozocin
Carmustine and Lomustine
Use: Treatment of tumors of brain & meninges
They have a severe
cumulative
High lipid solubility
cross the BBB
depressive effect on
the BM that starts
3-6 weeks after
initiation of
treatment
Streptozocin
Use: Treatment of insulinoma
Toxic to the β
cells of islets of
Langerhans

Used in medical research to
produce an animal model for Type
1 diabetes in large dose as well
as Type 2 diabetes with multiple
low doses.
Platinum complexes
Cisplatin
Carboplatin
Oxaliplatin
Cisplatin





Cisplatin is a water-soluble complex
containing a central platinum atom
alkylating agents : causing crosslinking of
DNA, which triggers apoptosis(programmed
cell death).
It is a nephrotoxic, renal function is
assessed by creatinine clearance and strict
regimens of hydration and diuresis must be
initiated
Cisplatin is one of the most emetogenic
chemotherapy agents
effective against testicular cancer
CISPLATIN
Cl
NH3
Pt
Cl
NH3
Cisdiaminedichloroplatinum II, CDDP
Mechanism of antitumour activity

Chloride atoms are replaced by water forming a positively
charged hydrated species that form strong covalent bonds with
electron rich atoms in nucleic acids and proteins resulting in:


DNA interstrand cross-links
DNA intrastrand cross-links
DNA-protein cross-link

Monofunctional and Bifunctional alkylation

CISPLATIN
Cl
H20+
NH3
Pt
HCl
20+
NH3
Cisdiaminedichloroplatinum II, CDDP
CDDP-INDUCED ORGAN TOXICITY
* Nephrotoxicity
* Neurotoxicity
* Cardiomyopathy
* Hepatotoxicity
CLINICAL TREATMENT OF CDDP-INDUCED
NEPHROTOXICITY
1- Intensive hydration and diuresis.
2- Dosing according to kidney function.
- BUN
- Serum creatinine
- Creatinine clearance
3- Avoiding concomitant use of other
nephrotoxic drugs.
4- Employing New Analogues
- Carboplatin
- Oxaliplatin
Broad-spectrum agents, fighting solid tumors:
breast, ovarian, testicular, lung, bladder cancers
Cisplatin
Carboplatin
1. Severe N/V
2. Dose-related
nephrotoxicity (Rx
hydration, mannitol)
3. Neurotoxic; peripheral
neuritis +Ototoxicity
4. Less Myelotoxic
1. Much less N/V
2. Much less nephrotoxicity
3. Less risk of peripheral
neuropathy , ototoxicity
4. It is more myelotoxic
dose-limited toxicity
blood cells decrease
dramatically, sometimes
as low as 10% of its
usual production levels.
Oxaliplatin
A
new member of this class with
better pharmacological profile
 Used in the treatment of
colorectal cancer with other
anticancer drugs.
Dacarbazine
 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 & vomiting
 Myelotoxicity
 Hepatotoxicity
Resistance to alkylating
agents
 Increased DNA repair
 Decreased permeability of
the drug
 Increased conjugation with
thiols (trapping agents)
Thank you