AC Flashcards
nitrogen mustard
regression of lymphoma
gastrointestinal and haematological toxicity
anti cancer drugs
many reduce cell growth and division in tumours
potential for:
invasion, vascularisation, metastatic spread
targetting cell growth
- prevent DNA replication by binding to nucleobases or impairing the DNA syntheisis machinery
- damage mechanisms of division ie mitotic spindle
- blocking pathways in cell growth activated by signals ie GF or hormones. ‘molecular targetted’ therapies - aimed at specific receptors or enzymes
1 +2 = common
3 = increasing interest
side effects of targetting rapidly proliferating cells
hair loss depression of gametogenesis - sterility bone marrow suppresion nausea and vomiting GI disturbances
tumours less responsive to anti proliferation drugs
centre of solid tumours
sarcomas - connective tissue - muscle or bone
carcinomas - epithelial cells ie breast or colon
lymphoma - lymph node or lymphoid tissye
target DNA
covalent or non covalent binding to inhibit DNA repication and transcription
antimetabolites inhibit DNA synthesis
inhib Topoisomerase enzymes, mitotic spindles, inhibit DNA replication and transcription
DNA alkylation
mitomycin C
nitrogen mustard
nitrosoureas
covalent
antimetab that inhibits DNA synthesis
inhibit normal precursor production
substitute purines and pyrimidines in nucleic acid synthesis
non covalent DNA inhibiting
cisplatin anthracyclin - (doxorubicin, daunomycin) mitoxantrone actinomycin D others
nitrogen mustard
mechanism
cytotoxic
dsDNA covalent
unstable Cl leaving groups
forms imonium ion at neutral or alkaline pH
form carbonium ion - electrophilic
react with guanine - become alkylated at N7
can react with another guanine at the opposite end of the drug ( similar cyclisation of the second side chain.
form interstrand crosslinks - inhibit strand separation
or interact with water - mono alkylated O6 alkylated - guanine, N7 guanine.
mispair with thymidine during replication - leading to GC->AT transversion.
mutation in DNA
alkylated G recruits BER - glycosylase then AP endonuclease. - creates single breaks in DNA
cyclophosphamide
lymphoid tumours
carcinomas in breast lungs ovary
orally given
needs to be metab by cytochrome p450 to become activated to a phosphoramide mustard
usually do not accumulate in particular tissue - non specific.
melphalan
L - phenylalanine mustard oral high bioavailability soluble phenylalanine is a precursor of melanin,so actively accumulated in melanocytes good for melanoma
