Mechanisms of anticancer agents ; drug resistance Flashcards
what are some current cancer treatments?
- surgery; highly successful for localised primary disease
- RT; external beam, intracavity, radioimmunotherapy
- Chemotherapy; applicable to systemic metastasised disease
- Immunotherapy; incl. vaccines
- Gene therapy; e.g. gene transfer
what is neoadjuvant chemotherapy?
to reduce the bulk of primary tumors prior to surgery or RT
what is adjuvant chemotherapy?
following primary surgery
what is fractional cell kill hypothesis?
a given drug conc. applied for a defined time period will kill a constant fraction of the cell population, independent of absolute number of cells
implications of drugs in cancer treatment
tumors best treated when they are small and treatment should continue until last cell is dead
what is the kineetic classification of anticancer drugs based on?
their effect on the cell cycle and if they are phase dependent or phase independent
what are some S-phase dependent drugs?
- ara C
- hydroxyurea
- methotrexate
- 6-thiogunaine
- raltitrexed
what are some G2/mitosis dependent drugs?
- etoposides
- vincas
- taxanes
what are somephase independent drugs?
- alkylating agents
- nitrosoureas
- mitomycin C
- anthracyclines
- 5FU
why do old drugs not work as well?
- limited by poor selectivity for tumors
- dose limiting effects on proliferating tissues
- drug resistance
haematological toxicity
most important dose-limiting toxicity for majority of cytotoxics
-myelosuppression ; risk of infection
- thrombocytopaenia (platelets) risk of haemorrhafe; may be delayed with some drugs (mitomycin C, nitrosoureas) or cumulative (chlorambucil)
GI toxicity
- nausea and vomiting; early onset (6 hours) or delayed up to two weeks (cisplastin) maybe alleviated by 5HT3 receptor antagonists (ondansetron) with dexamethasone
- diarrhoea (5FU, mitomycin C)
- mucositis (doxorubicin, 5FU, methotrexate)
other toxicities of chemotherapy
- alopexoa
- pulmonary toxicity
- cardiac toxicity
- renal
- bladder
- neurological
- local toxicity (at injection site)
tumor response; complete response
complete resolution of all measurable disease for at least one month
tumor response; partial response
50% reduction in product of two perpendicular diameters for on month or more
tumor response; stable disease
no change in size of measurable tumor over a period of one month or more
pathway of finding a new cancer drug
- target identification & validation ; molecular biology
- hit identification; screening, design
- lead optimisation; chemistry pharmacology; PK/PD
- preclinical development; manufactor, formulation, toxicology
- clinical trials; regulatory approval
how long does finding a new cancer drug take?
typically 12-15 years and >$500 million
what is looked at during target identification?
- prevalence and role in cancer vs normal organs
- does target provide a tractable drug target
what is looked at during validation of the drug?
genetics
- KO or KI mice
- RNA inerference
- dominant negatives
- antisense oligonucleotides
- inhibitory peptides/antibodies
what does hit identification of the drug involve?
compound acquisition
- natural products
- synthetic libraries of small molecules, peptides
- rationally designed molecules, antibodies
screening
- high throughput cell free assays (96, 384 well plates)
- cell based assays
what is the general lead optimisation cascade?
- cell free molecular screen; permeability, solubility, In-vitro, protein binding
- in vitro cell-based assays; paired cells with defined molecular pathologu, engineered isogenic pairs, diverse tumor panel
- phamacokinetics; blood levels, tissue levels
- maximum tolerated dose
- [hollow fibre tumor test (rapid in vivo acitvity read-out)]
- in vivo solid tumor; xenograft
- preclinical and clinical development
phase I clinical trials
- regulatory filing
- generally performed in cancer patients rather than healthy volunteers, usually because of low TI
- usually 20-30 patients
- what is max. tolerated dose? (PK important)
- what is dose limiting toxicity?
- antitumor activity NOT primary aim
- increasing emphasis on pharmacodynamics
what is phase II of clinical trials?
assess probabiliy of +ve risk to benefit ratio in Phase III.
generally single agent, single tumor type
- randomised control
- randomised disontinuation; all patients get same treatment, at 12 weeks , patients with stable disease randomised to placebo or active, evaluate at 24 weeks
dose escalation in phase I trials
- fundamental conflict; too fast = sudden jump from safe to life-threatening , too slow = large numbers of patients treated at ineffective doses, slower entry to phase II
- pharmacodynamics; molecular target
