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

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

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

MOA of alkylating agent Cross Intrastrand

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

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 Hemorrhagic Cystitis

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

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

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. NA-2-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: Characteristic toxicity: Myelosuppression N, V and diarrhea Carcinogenic Characteristic toxicity: Pulmonary fibrosis Skin pigmentation 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 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

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.

Cisplatin Carboplatin Oxaliplatin 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 Pt Cl NH3 H20+ Cl NH3 H20+ Cisdiaminedichloroplatinum II, CDDP

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

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 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.

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

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

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

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