Radiation - cause and cure of cancer

Question 1

What are the two main types of radiation?

Answer 1

• UV light long wavelength from sun > skin cancer

- ionising radiation - cosmic rays radiation > leukaemia

Question 2

What is linear energy transfer (LET)?

Answer 2

• efficiency of biological damage by radiation depends on energy deposited per unit length along path of radiation
• LET-energy lost per unit path-length
• densely ionising radiation - alpha particles, protons, neutrons
• high LET radiation more efficient than low LET biological damage, transformation and mutagenicity

Question 3

What are hydroxyl radicals?

Answer 3

• highly reactive, short-lived diffusion limited to 30nm distance
• main damaging agent as reacts with DNA to give :
• altered bases, loss of bases (abasic sites), single-stranded breaks, double-strand breaks
• cause cell death and carcinogenesis
• BUT UV radiation is carcinogenic largely through formation of thymine dimers

Question 4

Describe the concept of dose

Answer 4

• gray (Gy) = amount of absorbed radiation - 200,000 ionisations , 1000 DNA breaks
• curative - 0.1 Gy daily for 4-7 weeks
• different radiations have different biological effectiveness depending on LET, another unit
• dose equivalent (sieverts) : dose (Gy) x QF

Question 5

What are kill curves?

Answer 5

• ionising radiation produced single strand DNA breaks (esp. prevalent for low LET radiation) which can be repaired, and double strand DNA breaks (two adjacent single strand breaks) esp, high LET, that are ineffectively repaired

Question 6

How does different radiation affect human tissue?

Answer 6

• high sensitivity - thyroid, bone marrow, gonads
• moderate - breast, lung
• low - skin, stomach, bone, other tissue
• depends on rated of cell proliferation

Question 7

What factors are important for transformation?

Answer 7

• ionising radiation and UV are complete carcinogens
• initiation and promotion phases - free radicals involved in both
• cell proliferation needed to fix DNA damage
• enhanced by tumour promoters eg. TPA
• radioprotecters - glutathione SH group decreases effects of radiation - both lethality and transformation by scavenging free radicals

Question 8

Describe in vivo studies of leukaemia in mice

Answer 8

• carcinogenic potential depends on absorbed dose
• is greater per unit for high LET radiation
• low LET radiation less effective as dose falls not true for high LET radiation

Question 9

Ionising radiation and cancer

Answer 9

• no safe minimum dose
• incidence is proportional to dose
• recent studies of exposure verses cancer around chernobyl (rates of cancer far below what might be predicted) and cancer incidences in US states ( lowest cancer rates are in states with highest radiation exposure) suggests low level radiation exposure may be prime cellular repair mechanism - to hinder carcinogenesis

Question 10

Describe radiation in therapy

Answer 10

• x-rays used to treat 50% of cancer patients
• doses 10^6 greater than chest X-ray over 3-6 weeks
• x-irradiation produced DS breaks in DNA, causes cell death first or subsequent mitotic division
• normal tissue and tumour show radiation response proportional to proliferative turnover

Question 11

What is the role of fractionation?

Answer 11

• fractionated therapy - several daily 200 centiGy doses over several weeks
• why does fractionation maximise differences between normal and tumour cells? amplifies difference in response between tumour and normal tissue by:
• repair
• repopulation
• redistribution
• reoxygenation

Question 12

Describe the 4 Rs

Answer 12

• repair - extent of repair not equal in all tissues, slowly responding normal tissues have better repair than tumour cells
• repopulation - rate in tumour less than in normal tissues
• redistribution - small radiation dose preferentially kills most cells in radiosensitive phases of cell cycle. this produced synchronisation in most radio-resistant phase (G2/2 delay). Need to allow time for redistribution
• reoxygenation - tumours are hypoxic. Oxygen potentiates radiation killing by 3-4 fold by ‘fixing’ damage in DNA

Question 13

Is hypoxia good or not?

Answer 13

• tumours contain hypoxic cells
• causes resistance to radiation and anticancer drugs
• enhances cytotoxic effects of bioreductive drugs and enhances hyperthermia treatment
• bioreductive agents such as metronidazole and misonidazole target hypoxic cells:
• accumulate selectively in hypoxic tissue
• sensitize cells to radiation by fixing DNA damage
• are themselves toxic to cancer cells
• toxic side-effects have limited use in patients
• concept of ‘stealing’ use of vasodilator to induce hypoxia in tumour
• target these cells

Question 14

What is photodynamic therapy?

Answer 14

• heamatoporphyin phososensitizer accumulates preferentially in cancer cells - Use red laser light penetrates tissue

Question 15

What is brachytherapy?

Answer 15

• radioactive substance close to tumour

- radio-labelled antibodies - detect tumour spread