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Copyright
All images in this presentation are the property of Jane Hanrahan unless otherwise referenced.
References http://omlc.ogi.edu/spectra/PhotochemCAD/html/bilirubin.html, accessed 14/07/06 McDonagh et al., Science, 208, 1980, 145-151. http://www.psoriasis.org/about/psoriasis/ Accessed 14/070/06 Edelson, R. L. Scientific American, 68-75, 1988. http://www.bundp.net/iframes/qlight/qlight_text_penetration.htm Accessed 15/07/06 http://www.fda.gov/ohrms/dockets/ac/03/briefing/3983B2_02_PhotoCure-Briefing%2
After oral administration of 8-MOP, patients become gradually reactive to UVA and therefore to photochemotherapeutic treatment. Patients are maximally reactive 2-3 hours after ingestion of the drug.
Treatment TimeU
VA
Sen
siti
vit
y
Hours1 2 3 4 5 6 7 8
25
0
50
75
100
MA
XIM
UM
SEN
SIT
IVIT
Y
Mechanism of Action
4’,5’
Edelson, R. L. Scientific American, 68-75, 1988.
Photoreaction between
Psoralens
and DNA Ground state intercalation of psoralen in the dark Absorption of a photon by the 4’,5’-double bond or
3,4-double bond of psoralen Photoreaction between 4’,5’-double bond or the
3,4-double bond of the furan ring of the psoralen molecule and the 5,6-double bond of the pyrimidine base (thymine) to give a monofunctional adduct
Absorption of a photon by the 3,4-double bond of psoralen in the 4’,5’- monofunctional adduct
Photoreaction between 3,4-double bond of the pyrone ring of the psoralen molecule and the 5,6-double bond of a second pyrimidne base (thymine) giving a bifunctional adduct
Interaction between 8-MOP
and DNAThymine 8-Methoxypsoralen
Dark Weak Intercalation
UV-A
UV-A
4’,5’-Monoadduct 3,4-Monoadductor
Effects of PUVA
Phototoxic effect on skin
ErythemaInduction of dark pigmentation
Antiproliferative effect
Inhibition of growth or lethal effect (at high doses) on bacterial and mammalian cellsInhibition of DNA, RNA and protein synthesisInhibition of synthesis of epidermal DNA in mouse skinInhibition of infectivity of DNA viruses
Mutagenic effect
Causes mutations in a variety of micro-organisms & cell lines eg Eschericia coli, Sacchromyces cerevisiae, Sarcina lutea, Salmonella typhimurium & Chinese hamster cells
Photocarcinogenic activity
Photocarcinogenic activity on mouse skinRecent studies show increase in BCC in PUVA patientsInhibition of EGF cell binding
Other effects Alteration of immune system
Photodegradation of 8-MOP
Photodynamic Therapy (PDT)
Evolving therapy for treatment of cancers, psoriasis, vascular occlusion and macular degeneration
Involves administration of a photosensitiser followed by irradiation with visible light
Photosensitiser is often a porphyrin derivative Optimal tissue penetration occurs between 650-
800 nmUptake of photosensitisers is selective for
tumour cellsFirst generation photosensitisers have
several problems in practiceMany second generation photosensitisers
5-Aminolevulinic acid (ALA)Stimulates the synthesis protoporphyrin IX,
(PpIX) the immediate precursor to haem and an endogenous photosensitiser
Can be administered systemically or topically
Optimal concentration reached in 2-4 h max = 630nm Concentration in tumour can be measured
using fluorescenceRapidly undergoes photobleachingHydrophillic nature of ALA restricts skin
penetration -this can be overcome by use of esters
eg Metvix, Methyl ALA, approved for non-melanoma skin cancers and pre-cancerous growth in many countries
Synthesis of Protoporphyrin
IX
PpIX rate of formation is dependent on synthesis of ALA from glycine and succinyl CoA which is governed by -ve feedback by the concentration of free haem. Since conversion of PpIX to haem is relatively slow, administration of exogenous ALA bypasses the -ve feedback.
Haem synthesis in tumour cells is slower, allows PpIX to accumulate
DNA, to directly cause double strand breakage Water, causing the formation of free radicals in the
cell’s aqueous environment, leading to radical attack on DNA
Radiotherapy
Different radiation types have different energy deposition rates or Linear Energy Transfer (LET) which lead to different Relative Biological Efficiencies (RBE)
a + b radiation have high LET g + X rays have low LET
Clonogenic cell survival curves for cultured mammalian tumour cells irradiated with increasing doses of different quality LET beams. The RBE decreases with dose. The surviving fraction is measured by soft agar assay
100
10
1
1 2 3 4 5 6 7 8
RBE 5.6
RBE 3.3
Low LETHigh LET
Radiation dose (Gy)
Surviving fraction%
Irradiated water
Physical Stage
H2O H2O+ + H2O* + e-
H2O+ + H2O H2O+ + •OH
H2O+ + e-
H2O* H• + •OH
H2 + O•
radiation
Irradiated Water
Chemical Stage
•OH + •OH H2O2
•OH + e- -OH
•OH + H• H2O
H3O+ + e-aq H• + H2O
H• + H• H2
Radiation Therapy & Oxygen
Oxygen is an important mediator because it reacts efficiently with free radicals to “fix” the damage
Oxygen enhancement ration (OER) compares cell kill with and without Oxygen
Radiation sensitiser (oxygen mimetic) needed for hypoxic tumours
Radiation sensitisers
Misonidazole Razoxane
Summary
Treatment of neonatal jaundice PUVA therapy for psoriasis Photodynamic therapy Radiochemotherapy of tumours