cancer chemotherapy 1- alkylating agents

examples of an alkylating agent

• cyclophosphamide- nitrogen mustard

• carmustine (BCNU)- nitrosoureas

• thiotepa- aziridines

• busulfan- alkyl sulfonate

• procarbazine- monoalkulating agents

what are nitrogen mustards derived from

sulfur mustards

what are nitrogen mustards seen to cause

• leukopenia

• bone marrow aplasia

• lymphoid dissolution

• ulceration of the GI tract

what is leukopenia

destruction of white blood cells

what happened to the first person treated with nitrogen mustard

• suffered from lymphosarcomas

• tumours receded after 4 days

• but patient died 3 weeks later due to white blood cell count being down to 200/l

why is an aniline mustard used

electrons can spend more time around the benzene ring- delocalisation

where is the predominant crosslink in nitrogen mustards

between the N7 guanine on 2 strands- inter strand crosslink

what does the nitrogen mustard inter strand crosslink in DNA do

stops enzymes such as DNA polymerase being able to separate the strands and thus stops replication

what sort of ion does the nitrogen mustard form

aziridinium ion

what does the aziridinium ion do

alkylates the N7 guanine

what 2 types of crosslonkng can occur in the mechanism of alkylation

• intrastrand- outside strand

• interstrand- in-between 2 strands

what has inter strand cross linking been correlated with

anti tumour potency

how can cancer cells become resistant to alkylating agents

• increased expression of glutathione-S-transferase and levels of glutathione- drug attaches to glutathione and becomes inactive and is removed

• increased expression of excision repair enzymes

• changes in drug uptake- could take less drug in and pump more drug out

how can chemotherapy overcome cancer cell resistance

by blocking glutathione production

what are the target tumours for alkylating agents

• mechlorethamine- Hodgkins lymphoma and other lymphomas

• melphalan- multiple myeloma

• chlorambucil- chronic lymphocytic leukaemia

toxicity of alkylating agents

• tend to be non-cell cycle specific but target any proliferating cell

• nitrogen mustards- acute- nausea and vomiting, delayed- bone marrow depression

• nitrosoureas may induce leukaemia

• cisplatin- major nephrotoxicity

what is the most frequently used drug in the clinic

cisplatin

what is cisplatin used in the treatment of

• testicular, ovarian, head and neck, lung and bladder cancers

• essentially curative in testicular cancer

what type of complex is cisplatin

square planar complex of platinum