1. alkylating agents

2. Alkylating Agents Mechanism of Action

4. Alkylating Agents (continue)
DNA Alkylation will interfere with transcription and even replication of DNA.
The main effect made manifest during S phase, resulting in a block at G2 and subsequent cell death.
Main side effects:
Bone marrow depression with leukopenia and thrombocytopenia
GIT disturbances
Depression of gametogenesis (mainly in men), leading to sterility

5. Alkylating Agents Legend Nitrogen Mustards Ethylenimines Nitrosoureas
Alkyl Sulfonates
Cyclophosphamide
Thiotepa
Busulfan
Carmustine
CCNS
Legend
Drug Class
Sub-class
Prototype Drug

6. 1 - Nitrogen Mustards
They are related to sulphur mustard, the “mustard gas used during the First World War:
Mechlorethamine
Cyclophosphamide & Ifosfamide
Melphalan
Chlorambucil

7. Nitrogen Mustards

8. Mechanism of Action

9. A. Mechloroethamine The most rapidly acting alkylating agent.
After i.v. injection, it rapidly undergoes chemical transformation and presents in active form for few minutes. So that it is given locally by injecting the drug into the arterial blood stream supplying the treated tissue.

10. Mechloroethamine (continue))
Therapeutic uses:
Hodgkin’s disease: Alone or in combination with other antineoplastic drugs MVPP (mechloroethamine, vincristine, procarbazine, prednisone).
Solid tumors like breast, prostate and ovarian carcinoma (but alkylating agents of intermediate or slower reactivity are preferable)

11. Mechloroethamine (continue)
Side effects:
Nausea and vomiting.
Myelosuppression, leukopenia and thrombocytopenia.
Herpes zoster is frequently associated with treatment.
Menstrual irregularity in females.
Alopecia and skin rash.

12. B. Cyclophosphamide The most commonly used alkylating agents.
It is inactive until metabolized in the liver by P450 mixed function oxidases.
Ifosfamide is another analogue of cyclophosphamide that is activated by hydroxylation.
Both are administered orally

13. Cyclophosphamide Metabolism
Hemorrhagic cystitis resulting from toxic metabolite, acrolein, can be prevented with MESNA, mercaptoethane sulfonate, which provides electrons from sulfhydryl group. To prevent DNA repair by guanosine-O6-alkyl-a-transferase (GOAT), O6-benzyl guanine is given.

14. Cyclophosphamide Therapeutic uses:
Hodgkin’s disease and other lymphomas (alone or in combination with other drugs).
In combination with 5-fluorouracil and MTX as adjuvant therapy after surgery of breast cancer.
Carcinoma of lung, breast, cervix and ovary.
Used as immunosuppressant.

15. Cyclophosphamide Side effects:
Urinary tract haemorrhagic cystitis due to acrolein. So the patient should be well hydrated and treated by N-acetylcysteine or MESNA (sodium-2-mercaptoethane sulfonate). These agents interact specifically with acrolein, forming non-toxic compound. The dose of mesna = 23% of cyclophosphamide dose and taken 17 min before and 4-8 hr after cyclophsphamide dose.
Bone marrow depression
Nausea and vomiting
Alopecia and testicular atrophy

16. C. Melphalan Can be taken orally in treatment of multiple melanoma.
Phenylalanine derivatives of nitrogen mustard.
Therapeutic uses:
Can be taken orally in treatment of multiple melanoma.
In ovarian carcinoma (equal to cyclophosphamide)
Less effective in treatment of breast cancer.
Side effects:
Mainly haematological toxicity
Nausea and vomiting
No alopecia (useful in woman)

17. D. Chlorambucil
Aromatic derivatives of nitrogen mustard. It is the slowest acting nitrogen mustard in clinical use.
Therapeutic uses:
The treatment of choice in chronic lymphocytic leukemia (giving orally).
In treatment of breast, ovarian and testicular carcinoma.
Side effects:
Moderate and rapidly reversible myelosuppression.
Amenorrhea.
Pulmonary fibrosis.
Dermatitis.
Hepatotoxicity.

18. Alkylating Agents Legend Nitrogen Mustards Ethylenimines Nitrosoureas
Alkyl Sulfonates
Cyclophosphamide
Thiotepa
Busulfan
Carmustine
CCNS
Legend
Drug Class
Sub-class
Prototype Drug

19. 2. Alkylsulfonates: Busulfan
It is a unique in that it has No pharmacological action other than myelosuppression.
It depresses the formation of granulocytes and platelets in low dosage and red cells in higher dosage.
It has little or no effect on lymphoid tissue or the gastrointestinal tract. It is accordingly used in chronic granulocytic leukemia.
A high dose of busulfan in combination with high dose of cyclophosphamide is used to prepare the patient with acute leukemia for bone marrow transplantation.

20. Busulfan Side effects: Myelosuppression (mainly thrombocytopenia).
Nausea, vomiting & diarrhea.
Sterility and amenorrhea.
Fetal malformation.
Hyperuricemia: Extensive purine catabolism accompanying a rapid cellular destruction leads to renal damage due to precipitation of urates. The concurrent use of allopurinol is recommended to avoid this complication.

22. Alkylating Agents Legend Nitrogen Mustards Ethylenimines Nitrosoureas
Alkyl Sulfonates
Cyclophosphamide
Thiotepa
Busulfan
Carmustine
CCNS
Legend
Drug Class
Sub-class
Prototype Drug

23. 3. Nitrosoureas Carmustine Lomustine Semustine
Non-cross reactive with other alkylating agents
All require biotransformation by nonenzymatic decomposition
Highly lipophilic and cross the BBB therefore Tx Brain Tumors
Streptozocin-Tx insulin secreting islet cell carcinoma of the pancreas

24. Nitrosoureas
They are acting both by alkylation and by other unknown mechanisms.
The active alkylating moieties are formed by spontaneous non-enzymatic degradation.
They are highly lipophilic and so can cross the blood brain barrier. So they are used in treatment of meningeal leukemia and brain tumors (Gliomas).

25. Nitrosoureas Therapeutic uses: Hodgkin’s diseases and other lymphomas.
Meningeal leukemia and in primary and metastatic tumors of the brain.
Gastrointestinal, breast and renal cell carcinoma

26. Nitrosoureas Side effects:
Profound myelosuppression restrict their therapeutic uses.
Long-term treatment produces renal failure (especially with semustine).
Interstitial pulmonary fibrosis.

27. Drug Therapy of Glioma Carmustine Stereotactic delivery of Carmustine
Gliadel Carmustine wafer
Temozolomide

28. Temozolomide (Temodar)
This medication is used to treatment of GLIOMA (astrocytoma). The drug is taken by mouth in capsule form. Your full dose may contain two or more different strengths of temozolomide capsules. Take your dose at bedtime, with a full glass of water, on an empty stomach. Do not chew or open the capsules. If a capsule opens or breaks, be careful not to get the contents on the skin around your eyes, nose, or mouth. Temozolomide is usually given once daily for 5 days. The treatment may be repeated every 28 days.
Temozolomide is in a class of drugs known as imidazotetrazine derivatives. It slows or stops the growth of cancer cells in your body. The length of treatment depends on how well your body responds to the treatment.

29. Alkylating-Related Agents
Dacarbazine
Cisplatin & Carboplatin
Mechanism of Action involves alkylation
Cisplatin-an inorganic metal complex, kills cells in all phases of the cell cycle thru cross-linking

30. 1. Dacarbazine Therapeutic uses:
It is activated by N-demethylation in the liver and the resulting compound is subsequently cleaved in the target cell to release an alkylating derivative.
It inhibits the synthesis of RNA and protein more than the synthesis of DNA.
Therapeutic uses:
In Hodgkin’s disease alone or in combination with doxorubicin, bleomycin and vinblastin.

31. Dacarbazine (cont.) Side effects: Nausea and vomiting.
Myelosupression (leukopenia & thrombocytopenia).
Flu-like syndrome (chills and fevers).
Hepatotoxicity and neurotoxicity.
Alopecia and facial flushing.

32. 2. Cisplatin & carboplatin

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

34. 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

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

37. Cisplatin-INDUCED ORGAN TOXICITY*
* Neurotoxicity (Ototoxicity)
* Cardiomyopathy
* Hepatotoxicity
Nephrotoxicity

38. 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

39. 2. Cisplatin & carboplatin
They are water-soluble platinum coordination complexes.
When it enters the cell, chloride ion dissociate leaving a reactive diamine-platinum complex which react with water (aquation reaction) and then interacts with DNA.
They are very effective in treatment of solid tumors of the testes and ovary.
The main side effects of cisplatin are nephrotoxicity & ototoxicity while carboplatin is more myelotoxic.
Nephrotoxicity may be prevented by hydration and SH- containing compounds.