Cancer Chemotherapy Flashcards
what are the 3 main approaches to dealing with established cancers?
- surgical excision
- radiotherapy
- chemotherapy
what are the 4 types of traditional agent?
- alkylating agents
- antimetabolites
- cytotoxic antibiotics
- plant derivatives
what are the major groups of alkylating agents?
- nitrogen mustards
- ethylemimines
- alkylsulphonates
- hydrazines and triazines
- nitrosoureas
- platinum based compounds
what is an example of a nitrogen mustard?
cyclophosphamide
what is an example of alkylsulphonates?
busulphan
what are features of busulphan?
- has a selective effect on bone marrow, depressing formation of granulocytes and platelets in low dosage and red cells in higher dosage
- little or no effect in lymphoid tissue or GIT
- used in chronic granulocytic leukaemia
what type of cancer is busulphan used against?
chronic granulocytic leukaemia
what are examples of nitrosoureas?
- lomustine
- carmustine
what are features of lomustine and carmustine?
- lipid soluble
- can cross blood-brain barrier
- used against tumours of brain and meninges
what type of cancer are lomustine and carmustine used against?
tumours of brain and meninges
what is an example of a platinum based compound?
cisplatin
what are features of cisplatin?
- water soluble, planar
- containing central platinum atom surrounded by 2 chlorine atoms and 2 ammonia groups
how does cisplatin work?
- action analogous to alkylating agents: when enters cell Cl- dissociates leaving reactive complex that reacts with water and then interacts with DNA
- it causes intrastrand cross-linking which results in local denaturation of DNA chain
what are the major groups of metabolites?
- antifolates
- antipyrimidines
- antipurines
what is an example of an antifolate?
methotrexate
what are features of methotrexate?
- folate analogue
- usually given orally, can be given IM, IV or intrathecally
- low lipid solubility so does not cross blood-brain barrier easily
- polyglutamated, can be retained within cells for weeks
what are some examples of antipyrimidines?
- fluorouracil
- cytarabine
- gemcitabine
what are features of fluorouracil?
- 5-FU
- interferes with thymudylate synthesis (DTMP)
- converted to fraudulent nucleotide FDUMP, cannot be converted into DTMP
what are features of cytarabine?
- analogue of cytosine but has arabinose and not ribose attached
- undergoes phosphorylation to give cytosine arabinoside triphosphate which inhibits DNA polymerase
what are features of gemcitabine?
an analogue of cytarabine
what are examples of antipurines?
- mercaptopurine
- thioguanine
- fludarabine
what are features of mercaptopurine?
converted to 6-mercaptopurine-ribose phosphate called “Lethal Synthesis”:
- inhibits a number of enzymes in de novo synthesis of purines
- fraudulent nucleotide
what are features of fludarabine?
in triphosphate form inhibits DNA polymerase
cytotoxic antibiotics
- anti-tumour antibiotics
- produce their effects mainly by direct action on DNA
what are examples of types of cytotoxic antibiotics?
- anthracyclines
- dactinomycin
- bleomycin
- mitomycin
what is the main anti-cancer anthracycline antibiotic?
doxorubicin
how does doxorubicin work?
- binds to DNA and inhibits both DNA and RNA synthesis
- main cytotoxic action appears mediated through an effect on topoisomerase II (whose activity markedly increases in proliferating cells)
what are features of dactinomycin?
- intercalates in minor groove of DNA between adjacent guanosine and cytosine pairs, interfering with movement of RNA polymerase along gene, thus preventing transcription
- similar action anthracyclines on topoisomerase II
what are features of bleomycins?
- metal-chelating glycopeptide antibiotics that degrade preformed DNA, causing chain fragmentation
- most effective in G2 phase and mitosis
what are features of mitomycin?
- after enzymic activation functions as bifunctional alkylating agent
- cross-links DNA
- may also degrade DNA through generation of free radicals
what are examples of plant derivatives?
- spindle poisons
- vinca alkaloids
- taxanes
- camptothecins
- etoposide
what do spindle poisons do?
affect microtubule function and prevent mitotic spindle formation
what are examples of vinca alkaloids?
- vincristine
- vinblastine
what do vinca alkaloids do?
- bind tubulin
- prevent polymerisation into microtubules
what are examples of taxanes?
- paclitaxel (taxol)
- docetaxel
what do taxanes do?
stabilise (freeze) microtubules
what are examples of camptothecins?
irinotecan
what do camptothecins do?
bind to and inhibit topoisomerase I
what do etoposides do?
inhibits mitochondrial function, nucleoside transport and topoisomerase II
what are the main drawbacks of current cancer chemotherapy?
- target cell proliferation, not more lethal properties of invasiveness and metastasis
- non-specific cell killers rather than being aimed at particular changes which make a cell malignant
- development of resistance to anticancer drugs (esp. multidrug resistance)
- some remaining cells (tumour stem), total elimination of malignant cells not possible using therapeutic doses, and host immune response often not adequate to deal with remainder
- patient compliance due to side effects, not completing therapy regimen
what are alternative approaches to cancer therapy?
- kill or remove malignant cells
- targeted cytotoxic agents
- specifically inactivate components of oncogene signalling pathway
- employ tissue-specific proliferation inhibitors
- enhance host immune response
- reverse drug resistance
- antisense oligonucleotides
- restore function of tumour suppressor genes
- inhibit tumour growth, invasion, metastasis
- inhibitors of anti-apoptotic factors
what anticancer drugs are used for B cell lymphomas?
rituximab
- targets B cell surface protein
what anticancer drug is used for breast cancer?
trastuzumab (herceptin)
- targets epidermal growth factor receptor
what anticancer drug is used for chronic myeloid leukaemia?
imatinib (gleevec)
- inhibits bcr-abl gene signalling pathways
what causes cancer?
- mutations in DNA resulting in production of altered cells which have changes in proliferating mechanisms
- changes in the DNA caused by covalent modification:
- spontaneous or genetic predisposition
- ionising radiation or UV radiation
- chemical carcinogens
what is replaced in the structure of the antimetabolite, fludaribine?
- F replaces H of adenosine
- arabinose replaces ribose
what is replaced in the structure of the antimetabolite, 5-FU?
F replaces H of uracil
what is replaced in the structure of the antimetabolite, gemcitabine?
F replaces H and OH on ribose ring
what is replaced in the structure of the antimetabolite, 6-mercaptopurine?
S substitute in purine
when are bleomycins most effective in the cell cycle?
G2
