Skin Plasma Kidneys Liver B B B ox PB-Alb O2O2 1O21O2 + PB B ox PB Process 2 Process 1 O2O2 Urine Bile- intestine B = bilirubinAlb = albumin PB = mixture of photoisomers of bilirubin B ox = mixture of photooxidaton products of bilirubin hh
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 Time UVA Sensitivity Hours 12345678 25 0 50 75 100 MAXIMUM SENSITIVITY
4’,5’ Edelson, R. L. Scientific American, 68-75, 1988.
Thymine 8-Methoxypsoralen DarkWeak Intercalation UV-A 4’,5’-Monoadduct 3,4-Monoadduct or
Phototoxic effect on skin Erythema Induction of dark pigmentation Antiproliferative effect Inhibition of growth or lethal effect (at high doses) on bacterial and mammalian cells Inhibition of DNA, RNA and protein synthesis Inhibition of synthesis of epidermal DNA in mouse skin Inhibition of infectivity of DNA viruses Mutagenic effectCauses 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 skin Recent studies show increase in BCC in PUVA patients Inhibition of EGF cell binding Other effectsAlteration of immune system
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
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 LET High LET Radiation dose ( Gy ) Surviving fraction %