Cancer chemotherapy Flashcards
what makes cancer cells special?
- uncontrolled proliferation
- loss of original function (anaplasia)
- invasiveness
- metastasis (malignant cells)
what are the treatments available for cancer?
- surgical removal
- irradiation
- chemotherapy with anticancer drugs
when is surgery used as a cancer therapy?
only:
- for solid tumours
- if non-metastasised
when is irradiation used as a cancer therapy?
only if localised
what is required to use chemotherapy as a cancer treatment?
selective toxicity
can the treatments be combined?
yes
what happens to a single cells after 30 doublings?
it gives a cell mass of 10^9 cells - 2cm in diameter
- detectable in skin or breast (80%)
- non-detectable in liver
how do normal cells become cancer cells?
through a change in DNA
what two main categories of genetic change are there?
- inactivation of tumour suppressor genes
- activation of photo-oncogenes to oncogenes
what is apoptosis of transformed cells?
- failed check points at cell division
- programmed cell death
what do most anticancer drugs do not do?
- de-differentiation
- invasiveness
- metastasis
what do cell cycle drugs attack?
only a subpopulation of the cancer cells
what are cell-cycle specific drugs?
drugs that are active only on dividing cells
what are cell-cycle non-specific drugs?
drugs also active on resting cells
what do solid tumours consist of?
- dividing cells - progressing through cell cycle
- resting cells - not dividing but could do so
- cells which can no longer divide but contribute to tumour size
what are dividing cells sensitive to?
cell-cycle specific drugs
what are resting cells insensitive to?
many drugs
also causes many relapses
how many chemotherapy drugs are there?
more than 90
what do chemotherapy drugs mainly affect?
cell division
what do anti-cancer drugs affect?
all rapidly dividing normal tissue
what are the general toxic effects?
- bone marrow suppression (red and white blood cells)
- loss of hair
- damage to gastrointestinal epithelium
- liver, heart, kidney
- in children, depression to growth
- sterility
- teratogenicity (damage to embryo)
what happens if a dose of chemotherapy drug kills 99.999% of all dividing cells in a tumour of 10^9 cells?
it still leaves 10,000 cells
what does chemotherapy drugs aim to?
total kill of these cells
why is it required a prolonged treatment?
to reduce chance of relapse from resting cells –> severe cumulative toxicity
what are the main classes of drugs?
- alkylating agents
- antimetabolites
- cytotoxic antibiotics
- microtubule
- steroid hormones and antagonists
what are alkylating agents?
- form covalent bonds with DNA
- interfere with both transcription and replication
- most alkylating agents have two reactive groups
- allow the drug to cross-link
· with one strand DNA
· across 2 strands of DNA
what are the types of alkylating agents?
- nitrogen mustards - derived from mustard gases
- cysplatin
- lomustine - can penetrate brain
- busulphan
what is mechlorethamine?
type of nitrogen mustard
- first anticancer chemotherapy drug
- blister agent
- used to treat Hodgkin’s lymphoma, non-Hodgkins lymphoma
- highly reactive- must be given in vivo
what is melphan?
- fusion of mechlorethamine with phenylalanine (precursor of melanin)
- might accumulate specifically in melanomas
- more stable
- absorption and distribution possible without extensive alkylation
used to treat multiple myeloma, ovarian and breast cancer
what is cyclophosphamide?
- high phophoramidase activity in some tumours
- specific in situ activation in tumour cells
- prodrug, activated in liver
- much less toxic
- aldehyde dehydrogenase protects against drug - in bone marrow, hepatocytes and intestinal epithelium
- used to treat many cancers of tissues low in aldehyde dehydrogenase
what is cisplatin?
- targets N7 of purine nucleotides
- resistance from
· nucleotide excision repair mechanism
· efflux transporters for Copper
what are antimetabolites?
drugs that interfere with nucleotide synthesis or DNAa synthesis
what are the nucleotide synthesis (antifolates)?
methotrexate, ralitrexed, pemetrexed
what are the nucleotide analogues?
5-fluorouracil, cytarabine (Ara-C), gemcitabine, fludarabine, capecitabine
what are the types of antimetabolites?
- folate antagonists: methotrexate
- pyrimidine analogues: fluoro-uracil
- pruine analogues: mercaptopurines
what are folate antagonists?
- higher affinity for dihydrofolate reductase than folic acid
- inhibition of tetrahydrofolate formation
- inhibition of purine/pyrimidine synthesis
- ultimately, halt to DNA and RNA synthesis
what are pyrimidine analogues?
- prevents thymidine biosynthesis
- stops DNA synthesis
what are purine analogues?
- converted into false nucleotides
- disrupt purine nucleotide synthesis
- may be incorporated into DNA, disrupting helix
what is cytarabine?
- sugar moiety of cytidine is arabinosine rather than ribose
- isolated from the sponge cryptothethya crypto
- cellular activation to ara-CTP
- S phase cell cycle specific
- inhibit DNA polymerases
- incorporation into DNA causes chain termination
what are cytotoxic antibiotics?
act mainly by a direct action on DNA as intercalates
- dactinomycin
what is dactinomycin?
- isolated from Streptomyces
- inserts itself into the minor groove in the DNA helix
- RNA polymerase function is disrupted
- common adverse drug reaction includes bone marrow suppression, fatigue, hair loss, mouth ulcer, loss of appetite and diarrhoea
what is Doxorubicin?
- from Streptomyces?
- inserts itself between base pairs
- binds to the sugar-phosphate DNA backbone
- local uncoiling
- impaired DNA and RNA synthesis
- now some 2000 doxorubicin analogues (anthracyclines) exist
what are microtubule inhibitors?
- isolated from Madagascar periwinkles
- bind to micro tubular protein
- block tubulin polymerisation
- block normal spindle formation
- disrupt cell division
what do steroid hormones do?
tumour may be responsive to a specific hormone which makes it regress
- prednisone
- prednisolone
what is prednisone?
- synthetic adrenocortical steroid hormone
- converted in the body to active form
what is prednisolone?
suppresses lymphocyte growth
what will an antagonist of the hormone do?
suppress growth
e.g. tamoxifen - antagonist of oestrogen receptor
what are some breast cancers?
- oestrogen dependent
- oestrogen stimulates their growth
- can be treated with Tamoxifen
what are most prostrate cancers dependent on?
stimulation by testosterone
what could the prostrate cancer treatment be?
testosterone receptor antagonists
- e.g. glutamine (Drogenil)
- now replaces by bicalutamide (casodex)
what are pituitary downregulators for prostrate cancer?
- LHRH agonists inhibit release of Luteinising hormone (LH)
- LH normally stimulates testes to produce testosterone
- result: reduced testosterone release, reduced cancer growth
