Alkylating agents

Alkylating agents

1. Alkylating Agents Dr. Mohammed Fathy, MD Lecturer of Clinical Oncology Zagazig University

2. Type Introduction Cycle specific Phase non-specific

3. Mechanism of action Introduction (Cont.,) Alkylation of guanine Intermediates Alkyl groups Guanine residue Alkylating Agents Adduct Cross Link DNA RNA Protein Amino Carboxyl Sulfhydryl Phosphate

4. Mechanism of action Introduction (Cont.,) Adduct Interstrand Cross Link Intrastrand Cross Link Breakage of DNA strands Damage of DNA templates DNA-Protein Cross Link

5. Resistance Introduction (Cont.,) Conjugation with GSH DNA Damage Repair

6. Include Introduction (Cont.,) Cyclophosphamide Ifosfamide Chlorambucil Melphalan Busulfan Nitrogen mustard Carmustine (BCNU) Lomustine (CCNU) Bendamustine Nitrosoureas Dacarbazine Procarbazine Temozolomide Cisplatin Carboplatin Oxaliplatin Platinum Thiotepa Streptozocin Amsacrine

7. Indications Cyclophosphamide Breast CAF FAC CHOP FEC CEF AC EC CMF Lymphoma Metabolism Acrolein Excretion Urine Toxicity Myelosuppression Dose Limiting Hemorrhagic cystitis Headache Finger nail hyperpigmentation Metallic taste during injection Sneezing or cold sensation in nose Administration Large amount of fluid

8. Cyclophosphamide (Cont.,) Endoxan (Baxter) Trade name Cycram (EUP ) Supplied as Vials Tablets 200 mg 1000 mg 50 mg Storage below 25 o C Reconstitute NS Shake well Dilute NS, D5% Reconstituted solution Stable for 48 hours at 25 o c, 6 days upon refrigeration Protect from light

9. Indications Ifosfamide ICE Lymphoma Metabolism Excretion Toxicity Myelosuppression Dose Limiting Hemorrhagic cystitis Sarcomas Holoxan+Adri Relapsed Germ cell TIP Acrolein Urine Neurotoxicity Administration Aggressive concomitant hydration (2 to 4 L/day) Mesna Monitor urine for hematuria

10. Ifosfamide (Cont.,) Holoxan (Baxter) Trade name Ifos (EUP) Supplied as Vials 1 g 2 g Storage below 25 o C Reconstitute Sterile water Shake well Dilute NS, D5% Reconstituted solution Stable for 24 hours upon refrigeration Contain powder

11. Indications Cisplatin Cisplatin+vepside Lung Cancer Excretion Toxicity Cumulative renal insufficiency Dose Limiting Nausea & Vomiting Administration Cisplatin+vinorelbine Bladder cancer Cisplatin+Gemictabine Cisplatin+Paclitaxil Cipslatin+Gemictabine+Paclitaxil Lymphoma DHAP Urine Native drug Peripheral sensory neuropathy Ototoxicity Monitoring Mg, Ca Antiemetics Hydration & diuresis Amifostine cytoprotection Audiometry 40 mg/m 2 urine output of 100 to 150 mL/h Frusemide & Manitol IV fluids + Mg+Ca

12. Cisplatin (Cont .,) Trade name Unistin (EUP) Supplied as Vials 10 mg 50 mg Storage below 25 o C Reconstitute Sterile water or NS Dilute NS, never use D5% alone Reconstituted solution Stable for 24 hours at room temperature. Do not refrigerate reconstituted solution, Use immediately if mannitol is added to solution Contain powder or solution Cisplatine (Mylan) Platinol (Bristol-Myers Squibb)

13. Indications Carboplatin Ovarian cancer Toxicity Dose Limiting Hypersensitivity Carboplatin+Paclitaxel Myelosuppression Lymphoma ICE

14. Carboplatin (Cont.,) Trade name Supplied as Paraplatin ( Bristol-Myers Squibb) Carbotinol ( EUP) Carboplatine (Mylan) Vials 150 mg 450 mg Storage below 25 o C Reconstitute Sterile water or NS or D5% Dilute D5% Reconstituted solution Stable for 8 hours at room temperature

15. Oxaliplatin Indications Colorectal cancer FOLOFX XELOX FOLFORINOX Pancreatic cancer FOLFORINOX Gastric cancer EOF EOX Toxicity Dose Limiting Excretion Urine Acute dysesthesias Persistent peripheral neuropathy Allergic reactions Administration Not be mixed é alkaline drugs or media (basic solutions of fluorouracil) Avoid exposure to cold

16. Oxaliplatin (Cont.,) Trade name Supplied as Eloxatin (Sanofi Aventis) Oxaliplatine (Mylan) Vials 50 mg 100 mg Storage at 2-8 o C or below 25 o C Reconstitute Sterile water or D5% Dilute 250-500 mL D5% , never use NS . Reconstituted solution Stable for 24 hours at room temperature

17. Dacarbazine Indications Hodgkin lymphoma ABVD Toxicity Dose Limiting Excretion Urine Myelosuppression Flulike syndrome Administration Sarcomas AD MAID Malignant melanoma Neuroblastoma Metabolism Inactive Pain along injection site Withdrawing blood into drug‐filled syringe before injecting mixture reduces pain of injection

18. Dacarbazine (Cont.,) Trade name Supplied as DTIC Dacrabazine (medac) Vials 200 mg 5 00 mg Storage at 2-8 o C or below 25 o C Reconstitute Sterile water Dilute D5% , NS Reconstituted solution Yellow & should be discarded if the solution turns pink or red 1000 mg Avoid exposure to light

19. Temozolomide Indications GIII & GIV Astrocytomas Toxicity Dose Limiting Myelosuppression Photosensitivity Nausea & vomiting  S.GOT & S.GPT

20. Temozolomide (Cont.,) Trade name Supplied as Temodal (MSD ) Capsules 1 00 mg 250 mg Storage below 25 o C One hour before meal Never open or chewed