Cytotoxic chemotherapy, radiotherapy and drug resistance II Flashcards
What is drug resistance?
- most important reason for cancer treatment failure
- genetic instability of tumours enables adaptation of environmental changes
- heterogeneity, low growth fraction and slow doubling time of most solid tumours = low fractional cell kill
- hypoxia reduced drug access and tumour sensitivity to many drugs and radiation
What are the 3 groups of chemosensitivity of cancer?
- group 1: sensitive, cures are common - burkitts lymphoma, acute lymphoblastic leukaemia in children
- group 2: moderately sensitive, may prolong survival - ovarian cancer, breast cancer
- group 3: resistant, no definite effect on survival - non small cell lung cancer, melanoma
What are the 2 forms of resistance?
- pharmacological - inc drug efflux, dec drug influx, cytoplasmic drug inactivation, gene amplification
- post target - inc DNA repair, inc tolerance, failure to undergo apoptosis
What are the cellular mechanisms of resistance?
- dec intracellular drug concentration
- inc metabolism and detoxification
- altered expression of target proteins
- enhanced DNA repair
- dec drug activation
- salvage pathways
- failure to engage cell death pathways
Give an example of decreased intracellular drug concentration
- permeability glycoprotein P-glycoprotein
= energy dependent efflux transporter, multidrug resistance - lung resistance protein (LRP)
- breast cancer resistance protein (BCRP)
- methotrexate, via defect in membrane carrier protein
What are some anticancer drugs which interact with p-glycoprotein?
Doxorubicin Mitoxantrone Paclitaxel Etoposide Vinblastine Topotecan Mitomycin C
Describe the MRP family multidrug resistance
- MRP1 (ABCC1) : 190kDa protein, 7 members identified
- organic ion transporters - anionic drugs, neutral drugs with glutathione
- MRP1 expressed in most normal tissues = no strong correlation with clinical drug resistance, no modulators in clinic yet
- MRP2 (cMOAT) may contribute to resistance to cisplatin
List drugs involved in increased metabolism and detoxification
- thiols, tripeptide glutathione
- alkylating agents
- cisplatin, carboplatin
- anthracyclines
- increased levels of cytidine deaminase
Describe drugs involved in enhanced DNA repair
DNA nucleotide excision repair - alkylating agents, platinum drugs
0^6 alkyl-guanine repair
DNA mismatch repair - loss of repair leads to increased resistance/tolerance
List some drugs involved in altered expression of target proteins
- dihydrofolate reductase (DHFR) - methotrexate
- thymidylate synthase - 5FU, over-expression due to gene amplification
- altered tubulin - vinca alkaloids
- altered topoisomerase
List some drugs involved in decreased activation of pathways
- deoxycytidine kinase, deficiency prevents activation of prodrug purine and pyrimidine
- hypoxanthine guanine phosphoribosyltransferase
- folylpolyglutamate synthetase deficiency
Describe the multiple resistance mechanisms to single drugs
- cisplatin - reduced membrane transport, increased DNA repair, increased GSH
- methotrexate - defect in reduced folate carrier protein
- etoposide - increased drug efflux, altered topoisomerase II
Describe multidrug resistance
- ABC transporter efflux pumps: PgP, MRP familty
- increased glutathione - alkylating agents, platinums
- topoisomerase II mutation = lower activity
- loss of p53/increased Bcl2
Describe the mechanism of action of cisplatin
- cisplatin enters nucleus and cross links two adjacent guanines
How is cytokinetic resistance overcome?
- increased dose intensity= cisplatin
- combination chemotherapy
- alternating non-cross resistant chemotherapy
- scheduled guided treatment
Describe combination chemotherapy
- acquisition of drug resistance in initially sensitive tumour is a random process
- probability of de novo drug resistance in any tumour population will increase with increasing numbers of cells
principles: drugs should all be active when used alone, have different mechanisms of action, have minimally overlapping toxicities
What are some examples of combination therapy?
- AL leukaemia - vincristine (tubulin inhibitor and interferes with mitosis) /prednisone (steriod) /doxorubicin (topo 2 inhibitor)
- Hodgkins - mustard/ vincristine/prednisone/ procarbazine
Describe biochemical modulation in drug resistance
- hypoxically activated drugs= misonidazole, E09
- inhibitors of DNA repair enzymes - aphidiocolin (inhibits DNA polymerase). PARP inhibitors (incl BRCA mutant breast cancer)
- inhibitors of drug detoxification - buthionine sulfoximine
List drugs to circumvent multidrug resistance
- calcium channel blockers = verapamil
- cyclosporins = cyclosporin A
- calmodulin inhibitors - trifluoperazine
- antioestrogen - tamoxifen
Describe methods to reduce host toxicity
- alteration of route of drug administration
- normal tissue recue
- haematopoietic growth factors
- peripheral stem cell rescue
List some novel approaches to overcoming drug resistacne
- ADEPT - antibody directed prodrug therapy
- modulation of tumour oncogene/suppressor gene expression
- modulation of signal transduction pathways
- ribozyme or antisense inhibition of resistance mechanisms
- NOT FULLY SUCCESSFUL - future ideas
