29) Treatment of Cancer 2 Flashcards
1) Main treatments for cancer
surgery
radiotherapy
chemotherapy
others (e.g. PDT)
2) Radiotherapy
utilises X-rays or radiopharmaceuticals (radionuclides) which act as sources of gamma rays
X-rays are delivered locally in a highly focused beam to avoid damage in healthy tissue
main radionuclides in use include Cobalt-60, Gold-198 and Iodine-131
Gold-198 concentrates in the liver and Iodine-131 is used to treat thyroid cancers as iodine accumulates in this gland
significant proportion of tumour cells are hypoxic (i.e. have low oxygen levels) so are less sensitive to damage by irradiation
therefore prior to and during radiation therapy, oxygen is sometimes given to sensitise the tumour cells to treatment
3) Photodynamic therapy
involves initial systemic administration of photosensitiser such as porphyrin derivative Photofrin which is selectively retained by malignant cells
after agent has localised, the tumour is irradiated with an intense light source of an appropriate wavelength which excites Photofrin
upon decay to its ground state, available oxygen is transformed into singlet form which is highly cytotoxic and damages tumour cells
by damaging endothelial cells, PDT restricts blood flow to the tumour
tumours in inaccessible organs and areas of the body can be easily reached through endoscopy and key-hole surgery techniques
4) Role of biological agents
monoclonal antibodies that target specific tumour antigens produced on the cell surfaces of several tumour types
5) Small-molecule chemotherapy
use of small low MW drugs to selectively destroy a tumour or limit its growth
6) Advantages and disadvantages of small-molecule chemotherapy
advantage is that low MW weight drugs normally pervade all tissues of the body and so can destroy cells in protected areas or in the process of metastases
disadvantages include unpleasant side effects of bone marrow suppression, hair loss and nausea and the rapid development of clinical resistance in most tumour types
7) Drug targets for cancer therapies
growth factors growth factor receptors adaptor proteins docking/binding proteins guanine nucleotide exchange factors phosphatases and phospholipases signalling kinases ribosomes targets for biological agents transcription factors histones DNA microtubules antigens for antibody targeting hormonal pathways target for biological agents
8) Sources of anticancer drugs
natural products serendipity clinical observation synthesis and screening structural biology/rational drug design synthesis/screening
9) Evaluation of novel anticancer agents
in in vitro tumour cell lines
only measures their cell killing ability (cytotoxicity) and/or other biochemical parameters
provides no indication of in vivo antitumor activity
however by studying panels of different tumour cell types, can indicate whether agent has selective toxicity towards particular tumour type which may in turn suggest suitable in vivo experiments
involve administering novel agents on tumour cells growing in porous fibres in mice or rats
human tumour xenograft assay most successful as human tumour fragments are transplanted into immunosuppressed rodents
10) Accessibility of drugs to different types of tumour cells
leukaemia cells are fully exposed to drugs in the blood stream, whereas solid tumours have a less reliable blood supply
small tumours are usually reasonably well-supplied and more susceptible to drug actions than large tumours which have poor capillary access particularly in their centres which can be hypoxic or even necrotic
brain tumours are particularly resistant to chemotherapy as few drugs are capable of crossing the blood brain barrier
11) Achieving selective drug toxicity
dependent upon discovery of exploitable biochemical differences between normal and tumour cells
such differences should allow for a more rational approach to drug discovery
exploiting genetic differences between tumour and healthy cells e.g. Mustards that bond covalently to GC sequences of DNA exploiting the fact that some oncogenic DNA sequences are GC rich
12) Detailed diagram of the cell cycle
M- prophase, metaphase, anaphase, telophase
G0
G1- growth and preparation for DNA synthesis
S- DNA replication
G2- preparation for mitosis and growth
13) Mechanism contributing to the development of resistance
decreased intracellular drug levels- could results from increased drug efflux or decreased inward transport
increased drug inactivation
decreased conversion of drug to active form
altered amount of target enzyme or receptor (gene amplification)
decreased affinity of target enzyme or receptor for drug
switching on/off biochemical pathways
enhanced repair of drug-induced defect
decreased activity of enzyme required for the killing effect
multidrug resistance whereby tumours become resistant to several often unrelated drugs simultaneously
multidrug resistance (MDR1) gene encodes ATP-dependent efflux pump, gene that may be amplified
14) Combination therapy
attempts to treat tumours with single agents are often disappointing
as a rule each drug included in a combination should be active as a single agent and have different toxic (dose limiting) side effects compared to others
multiple drug therapy enables simultaneous attack of different biological targets thus enhancing the effectiveness of treatment
15) Adjuvant therapies
sometimes necessary to co-administer the other agents that can either enhance activity as of the anticancer drug or counteract any side effects produced
in terms of adjuvants to reduce side effects, anti-emetics will often be administered to counteract nausea commonly associated with many chemotherapeutic agents
myelosuppression is more problematic as it can lead to increased risk of infection, so antibiotic and/or antifungal therapy may be required
steroids such as prednisolone may be co-administered with some anticancer agents to reduce severity of side effects
