Cancer (2) Anticancer Agents 1 Flashcards
Main approaches to cancer treatment
Surgery
Irradiation
Chemotherapy
Cancer cells characterised by
Invasiveness
>loss of recognition of normal restraints
>expression of matrix-degrading enzymes
Ability to metastasise
>secondary tumours distant from primary
>often through lymphatics
Tumour suppressor genes
Act as sentinels to detect DNA damage
E.g. p53
>gene most commonly mutated in human cancer (>50% cancers)
>if DNA damaged, p53 arrests replication
DNA damage > loss of p53 deactivation > cell cycle arrest > dna repair or irreversible dna damage >apoptosis
If p53 altered through mutation (loss of function)
DNA damage goes unchecked
>no repair
>loss of apoptotic removal of cells whose DNA is irreparably damaged
> Other mutations in cells will accumulate
cancer
Protooncogenes
Normally responsible for cell growth and differentiation
Mutation leads to abnormal growth
Exmaples >growth factors, >growth factor receptors >Members of growth factor signalling pathways >cell cycle transducers
E.g. Ras gene
Codes for Ras, a guanine nucleotide binding protein (GTPase)
- Ras-GTP = “on”
- Ras-GDP = “off”
Common component of many cell signalling pathways leading to proliferation
Mutations in Ras
Found in 20-30% human tumours
Reduced inactivation of Ras
>reduced intrinsic GTPase ability
>reduced susceptibility to GTPase activating proteins
Ras-GTP becomes predominant form
>constitutively activated
Cell divides in absence of growth factor binding
Principles of cancer chemotherapy
Exploit a difference between normal and tumour cells
>rate of growth (traditional)
>some other aspect of biology (contemporary)
Tumour growth may be exponential
>need near total removal of tumour cells for effective treatment
Log cell kill model
Cell destruction is first order i.e. constant fraction of cells killed
E.g. 10^12 cells in tumour, kill 99.99%
>10^8 cells after 1 cycle of treatment
>10^4 cells after 2 cycles
Side effects requires intermittent dosing
Intermittent dosing allows for
>tumour regrowth
>development of resistant cells
Resistant cells grow exponentially regardless of treatment
Principles of cancer chemotherapy
Therapeutic window
In practice, growth limited by blood supply to tumour
>angiogenesis
>current new target in therapy
“Resting” cells may be resistant to treatment
>tumour stem cells
Therapeutic window often non-existent
>dose for treatment is same or greater than dose giving side effects
> > Limits dose and duration of therapy
Principles of cancer chemotherapy
Selective toxicity
If selective toxicity is via rapid cell division
Toxicity will result from effects on other fast-dividing cells >bone marrow suppression >impaired wound healing >hair loss >gut epithelium damage
Classes of anticancer drugs
Cytotoxic drugs >alkylating agents >antimetabolites >anthracyclines >microtubule inhibitors
Drugs that exploit other aspects of tumour biology
>Hormones and related agents
>antiangiogenesis agents
>kinase inhibitors
Cytotoxic anticancer drugs
Kill cells
>damage DNA
>interfere with DNA synthesis
>mitosis
Cells that are traversing cell cycle more frequently
>i.e. rapidly dividing cells will be most affected
Alkylating agents
Bind covalently with nucleophilic cell components
>N7 and O6 of guanine
Many are bifunctional
>cross linking of DNA (intrastrand)
Cisplatin (alkylating agent)
Discovered by chance while examining effects of electric currents on bacteria
>bacteria at platinum electrode had reduced DNA synthesis
Used for testicular and ovarian cancer
>revolutionised treatment of testicular cancer in 1970s
Causes intrastrand cross linking
>denaturation of DNA
Cisplatin (MOA)
Two leaving groups (Cl)
Bis-alkylation causes intrastrand crosslinks between adjacent guanine residues
>denaturation of DNA
Trans-isomer inactive (although can still bind to DNA, cannot form crosslinks)
Cisplatin side effects
Nephrotoxic, neurotoxic
>causes dose-limiting sensory neuropathy (numbness)
Severe nausea and vomiting
>enhances nephrotoxicity
>can be controlled with ondansetron
(serotonin receptor 5HT3 antagonist)
Antimetabolites
Inhibit DNA synthesis pathways
>methotrexate
>5-flutouracil
Synthesis of thymidylate
Folate > dihydrofolate > tetrahydrofolate
Tetrahydrofolate + 2-deoxy uridylate (dUMP)
= 2-deoxy thymidylate (dTMP)
- enzyme is thymidylate synthetase
= required for new DNA synthesis
Methotrexate
Inhibits enzyme dihydrofolate reductase
(converts folate into dihydrofolate into tertahydrofolate - same enzyme)
Cells > “thymineless” death
Methotrexate MOA
Inhibts dihydrofolate reductase (DHFR)
Has higher affinity for DHFR than natural substrate (folate)
>prevents generation of tetrahydrofolate (FH4)
(FH4 is a cofactor in thymidylate production)
> Blocks thymidylate production
disrupts DNA synthesis
Methotrexate administration
Low lipid solubility, therefore does not cross BBB
Get bone marrow depression, gut epithelium damage
Resistance common (with all cytotoxic drugs) >use high dose + folate >why give folate? >>in many tumour types, differences in mechanisms uptake of folate into cell
5-Fluorouracil
Converted to false nucleotide
>5-fluorodeoxyuridine monophosphate (FdUMP)
FdUMP directly inhibits thymidylate synthetase
>inhibition of DNA synthesis
Administered with folate
>increases toxicity, as inhibited enzyme is a complex with FdUMP and cofactor derived from folate (make sure cell has enough folate to carry out this pathway to get cell cytotoxicity with the false FdUMP nucleotide)
Side effects:
>Gut damage and bone marrow toxicity
Anthracyclines
E.g. doxorubicin
Binds to DNA by interaclation
>sliding between base pairs
Affects the enzyme topoisomerase II
>required for DNA unwinding and rewinding to relieve supercoiling
>nicks and rejoins DNA
