Lecture 2: Alkylating Agents Flashcards
Alkylating Agents
Influence all stages of cell cycle
Originated from study of nitrogen mustard to suppress tumor lymphoid cells
Nitrogen mustards: cyclophosphamide-first gen
Nitrosoureas:lomustine
May act on non-dividing cells, can cross BBB
Cisplatin: Not really an alkylating agent
Treat testicular cancer and causes severe nausea and vomiting and can be nephrotoxic
Revolutionized the treatment of germ cell tumours
Nitrogen Mustards
Bifunctional Cl ether used to treat Hodgkin’s lymphoma(Mechlorethamine), chronic lymphocytic leukemia(chlorambucil) and multiple myeloma(Melphalan)
Alkylating Agent Mechanism
Form highly reactive, POSITIVELY CHARGED(electrophilic) intermediates
Alkyl groups bind covalently to DNA
Most are BIFUNCTIONAL: cause intrastrand linking and cross-linkage
Dose limiting: MYELOSUPPRESSION-neutrophils/leukocytes
Some are mutagenic
Form cyclisation to make unstable ethylene immonium cation-electrophilic
Reactive carbonium ion attacked by N7 of GUANINE= 7-alkylguanine
Cyclophosphamide(CPX)
First gen nitrogen mustard
Lymphoid and myeloid maligancies
Part of CMF treatment protocol:
C: CYCLOPHOSPHAMIDE
M: METHOTREXATE
F: FLUOROURACIL
SFX: myelosuppression, immunosuppression, hemorrhagic cystitis
Co-treated with MESNA to remove toxins(acrolein)
Acrolein: hemorrhagic cystitis-MESNA detox this
Used as a pesticide in Canada
Ifosfamide(IFO)
Lymphoid and myeloid malignancies
Part of IMF protocol after breast surgery:
I: IFOSFAMIDE
M: METHOTREXATE
F: FLUOROURACIL
SFX: Myelosuppression, hemorrhagic cystitis(ALWAYS GIVEN WITH MESNA)
Nitrosoureas
Ex. BCNU(carmustine: bifunctional agent), CCNU(lomustine: monofunctional agent)
Require liver activation
Both are LIPID SOLUBLE and can penetrate BBB-useful for brain tumours
SFX: Myelosuppression, Leukemogenic, Hepatotoxicity has also limited use
Busulfan an alkyl sulphonate
Bifunctional SO3CH3 groups
Cause Guanine-Guanine and Guanine-Adenine intra-strand crosslink
Selective effects on blood forming cells(decrease granulocytes, platelets, erythrocytes at high doses)
Used in high dose bone marrow transplant regimes-Chronic myelogenous leukemia(CML)
Largely replaced today by Imatinib
Triazines
decarbazine, temozolomide
- temozolomide is prodrug of dacarbazine
- Used for some glioblastomas and melanomas
- N-7 or O-6 position of guanine
Ethylenimines(thiotepa)
- lymphoma and breast, ovary,bladder cancers
- also used to treat malignant effusion(fluid collects in lung around heart)
Alkylating agent
Resistance to alkylating agents
Decrease transport across cell membrane(INFLUX)
Increase intracellular thiol concentration-too much GSH
Glutathione depletion enhances effects of alkylating agents
Increase enzymatic detoxification of reactive intermediates
Glutathione S-transferase
Alterations in DNA repair enzymes-enhance DNA repair
MAIN/BIGGEST source of resistance
DNA-repair enzyme
O-6-methylguanine-DNA methyltransferase(MGMT): if the MGMT promoter region is methylated, cell no longer produces MGMT and are therefore more responsive to alkylating agents
Methylation of MGMT promoter in gliomas is useful predictor of the responsiveness of tumors to triazine alkylating agents(LESS METHYLATED, LESS RESPONSIVE TO TREATMENT)
Platinum Complex(CISPLATIN)
DNA-reactive
Bifunctional
INTRASTRAND cross-link
First gets into cell-> conversion of Cl to H2O(+ charged intermediate can’t leave cell)->DNA reactive intrastrand crosslink
Platinated DNA is more difficult to repair than regular DNA
60-70% of adduct is guanine-guanine linked, but also bind adenine GpA
Cisplatin
Cell-cycle non-specific
Testicular cancer(PEB>90% cures)
Ovarian cancer
Other solid tumours
Renal toxicity(nephrotoxicity-DOSE LIMIT): Generate of ROS
Nausea and vomiting
Pre-medicated with antiemetic adjuvant therapy
Resistance is common: Decrease uptake and retention-pumped out cell actively
Increase DNA repair
Increase in production of cellular thiols-GSH(inactivated the activated cisplatin by forming complexes with it)
