What are the general characteristics of cell cycle specific agents?
Tumour specific Duration of exposure more important than dose
What are the different types of cell cycle specific agents?
Antimetabolites - impair nucleotide synthesis/incorporation Mitotic spindle inhibitors
What are some examples of antimetabolites?
Methotrexate - inhibits dihydrofolate reductase 6-mercaptopurine/cytosine arabinoside/fludarabine - incorporated into DNA Hydroxyurea - impaired deoxynucleotide synthesis
What are some examples of mitotic spindle inhibitors?
Plant derivatives; vinca alkaloids (vincristine/vinblastine), taxotere (Taxol)
What are the general characteristics of non-cell cycle specific agents?
Non-tumour specific; damage normal stem cells Cumulative dose more important than duration
What are the different types of non-cell cycle specific agents?
Alkylating agents Platinum derivatives Cytotoxic antibiotics
What are some examples of alkylating agents and how do they work?
Chlorambucil/melphalan Bind covalently to bases of DNA Produces DNA strand breaks (mutation) by free radical production
What are some examples of platinum derivatives?
Cis-platinum/carboplatin
What are some examples of cytotoxic antibiotics and how do they work?
Anthracyclines - daunorubicin/doxorubicin/ idarubicin DNA intercalation Impairs RNA transcription Strand breaks in DNA
What are some of the potential immediate side effects of cytotoxic drugs?
Affects rapidly dividing organs - bone marrow suppression, gut mucosal damage, hair loss
What are some examples of drug specific side effects?
Vinca alkaloids - neuropathy Anthracyclines - cardiotoxicity Cis-platinum - nephrotoxicity
What are some examples of drug specific long term side effects?
Alkylating agents - infertility, secondary malignancy Anthracyclines - cardiomyopathy
Why does chemotherapy sometimes fail?
Slow tumour doubling time Tumour sanctuaries Drug resistance mechanisms e.g. increased DNA repair in cis-platinum resistance
Why is intensifying chemotherapy limited and how can this be overcome?
Limited by myelosuppression Overcome by use of haematopoietic growth factors, combine myelosuppressive with non-myelosuppressive agents and intensify dose of active drugs + stem cell rescue
What are the potential sources of stem cells for transplantation?
Tissue source - blood versus bone marrow Patient source; autologous or allogenic (sibling, unrelated)