1. I. Alkylating Agents & Related Compounds

2. 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

3. Resistance may occur during treatment with alkylating agents
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

4. Major classes of alkylating agents
Nitrogen mustards
Nitrosoureas
Carmustine
Lomustine
Streptozocin
Cyclophosphamide
Mechlorethamine
Chlorambucil
Melphalan
Alkyl sulfonates
Related agents
Busulfan
Platinium analogues; Cisplatin,
Carboplatin, Oxaliplatin
Thiazines; Dacarbazine

5. MOA of alkylating agent
Cross
Intrastrand

6. DNA is unable to replicate
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

7. 1.Nitrogen mustards
Nitrogen mustards are related to the 'mustard gas' used during the first world war and caused severe myelosuppression

8. 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)

9. Cyclophosphamide Metabolism
Hemorrhagic Cystitis

10. Clinical uses of Cyclophoshamide
Hodgkin disease & other lymphomas
Ovarian cancer
Breast Cancer (CMF) Cyclophoshamide,
methotrexate & fluorouracil
Lung cancer

11. Other clinical uses of Cyclophoshamide
Cyclophosphamide is a potent immuno-suppressant drug used in:
(a) control of organ rejection after
transplantation
(b) disorders associated with altered
immune reactivity such as
intractable rheumatoid arthritis

12. Common adverse effects of Cyclophosphamide
Alopecia, Nausea & Vomiting, diarrhea
Amenorrhea, testicular atrophy & sterility.
Bone marrow depression
Carcinogenesis may appear years after therapy (acute leukemia)

13. 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”

14. 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. NA-2-mercaptoethane sulfonate (MESNA)
MESNA neutralizes the toxin acrolein, forming a non-toxic compound.

15. Chlorambucil
An alkylating agent used in treatment of chronic lymphocytic leukemia
Chlorambucil causes bone marrow depression and GIT upset
Chlorambucil is mutagenic

16. 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

17. 2-Alkyl sulfonates
Busulfan

18. 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

19. Busulfan Adverse effects: Characteristic toxicity: Myelosuppression
N, V and diarrhea
Carcinogenic
Characteristic toxicity:
Pulmonary fibrosis
Skin pigmentation
Adrenal insufficiency

20. 3-Nitrosoureas include a nitroso (R-NO) group and a urea.
Carmustine
Lomustine
Streptozocin

21. Carmustine and Lomustine
Use: Treatment of tumors of brain & meninges
High lipid solubility
cross the BBB
They have a severe cumulative depressive effect on the BM that starts 3-6 weeks after initiation of treatment

22. Streptozocin Use: Treatment of insulinoma
Toxic to the β cells of islets of Langerhans

23. 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.

24. Cisplatin Carboplatin Oxaliplatin
Platinum complexes
Cisplatin
Carboplatin
Oxaliplatin

25. 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

26. CISPLATIN Cl
NH3 Pt Cl
NH3
Cisdiaminedichloroplatinum II, CDDP

27. 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

28. CISPLATIN Pt Cl NH3 H20+ Cl NH3 H20+
Cisdiaminedichloroplatinum II, CDDP

29. CDDP-INDUCED ORGAN TOXICITY*
* Neurotoxicity
* Cardiomyopathy
* Hepatotoxicity
Nephrotoxicity

30. 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

31. Broad-spectrum agents, fighting solid tumors: breast, ovarian, testicular, lung, bladder cancers
Cisplatin
1. Severe N/V
2. Dose-related
nephrotoxicity (Rx
hydration, mannitol)
3. Neurotoxic; peripheral
neuritis +Ototoxicity
4. Less Myelotoxic
Carboplatin
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.

32. Oxaliplatin
A new member of this class with better pharmacological profile
Used in the treatment of colorectal cancer with other anticancer drugs.

33. Dacarbazine Treatment of melanomas Common adverse effects:
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

34. Resistance to alkylating agents
Increased DNA repair
Decreased permeability of the drug
Increased conjugation with thiols (trapping agents)

35. Thank you