Biomedical subjects
Publications and source records attributed to M C Berenbaum.
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The effects of pre-injection of mice with a novel perfluorodecalin-based emulsion on the responses to photodynamic therapy (PDT) using the photosensitizer, metatetra (hydroxyphenyl) porphyrin (m-THPP), have been studied. Injection of emulsion after m-THPP and before illumination (activating wavelength 648 nm) protected skin against PDT-induced inflammatory effects, as reflected by decreases (P less than 0.05) in vascular permeability and oedema formation. However, there was no protection against epidermal cell loss. In contrast, injection of emulsion before sensitizer had no corresponding effect. A fall in mean dermal temperature of up to 6 degrees C occurred in mice injected with emulsion 1-2.5 h before illumination suggesting a decrease in skin blood flow which would reduce oedema formation. Possible mechanism(s) for this apparent protective effect are discussed.
Four patients underwent intraoperative photodynamic therapy after surgery with meso-tetra-(hydroxyphenyl)-chlorin (mTHPC-PDT) for diffuse malignant mesothelioma. Preliminary procedures were performed in two patients in order to establish the efficacy of mTHPC-PDT and to optimise its tumoricidal effect. The tumoricidal effect was related to the mTHPC dose, light dose and the time interval between sensitation and activation. 0.3 mg kg-1 mTHPC activated after 48 h with 10 Joules cm-2 of non-thermal laser light at 650 nm resulted in a 10 mm deep tumour infarction, due to tumour vessel necrosis and thrombosis. The mTHPC tissue concentration was up to 14 times higher in the tumour than in normal tissues. Skin photosensitivity was mild, dose dependent and occurred 3 to 10 days after administration of mTHPC. According to the results obtained, intraoperative mTHPC-PDT was performed following pleuropneumonectomy in two, pleurectomy and lobectomy in one and pleurectomy in one patient. Ten Joules cm-2 were delivered to the diaphragm and the costophrenic sulcus and 5 Joules cm-2 to the remaining thoracic cavity. The postoperative course was marked by loss of appetite, fluid retention, hypoproteinemia and severe chest pain. One patient succumbed from aspiration pneumonia. The remaining patients developed no neural or vascular alterations and no bronchial stump insufficiency during follow-up. mTHPC-PDT following surgical tumour resection deserves further evaluation in good risk patients with diffuse malignant mesothelioma.
Subcutaneous and intracranial VMDk tumours were treated with photodynamic therapy (PDT) using a new sensitiser, m-THPP. Subcutaneous tumours were highly sensitive to PDT but intracranial tumours were much more resistant, requiring a 30-fold increase in sensitiser dose to produce equivalent levels of necrosis. Resistance of intracerebral tumours was not due to failure of the sensitiser to enter tumours. Necrosis of intracranial tumours was increased when mice breathed 100% oxygen during PDT while subcutaneous tumour necrosis was unaffected.
To study the effects of photodynamic therapy on the tissues of the tongue, 20 New Zealand White rabbits were injected intravenously with haematoporphyrin derivative. Their tongues and those of 2 controls were illuminated with 100 J/cm2 of red light from a copper vapour-pumped dye laser emitting light at 625 nm. The rabbits were sacrificed at intervals between 2 days and 12 weeks following treatment. Their tongues were examined histologically. Initially there was marked damage to mucosa, muscle and blood vessels. However, this healed by a mixture of regeneration and scarring.
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The effects of pre-treatment with a novel PFC emulsion on PDT-induced tumor necrosis have been studied in mice. Injection of emulsion either 2.5 hr or 24 hr before PDT did not affect the depth of tumour necrosis. However, pre-treatment with the emulsion appeared to protect skin against photodynamic damage although the mechanism(s) and active principle(s) involved were not identified. These results suggest that there may be specific advantages in using emulsified PFCs in conjunction with PDT which may be independent of changes in tumour oxygenation.
The requirements for activity in a tumour-photosensitizing drug are outlined. A series of metallo tetrasulphonatophthalocyanines are shown to be inactive in an in vivo assay of tumour photosensitization; however, some less water-soluble compounds (hydroxylated derivatives of octaethylchlorin and octaethylbacteriochlorin) are shown to possess promising activity.
Current cancer chemotherapy regimens may involve 20-30 or more independent variables, each affecting therapeutic response and toxicity. With standard response surface modelling methods, finding the optimum combination with as few as 10 variables entails testing over 1,000 combinations, so these methods do not provide a feasible approach to such problems. However, they may be tackled by direct search methods (DSM), i.e. stepwise searches of the response surface. Experiments were carried out in advanced L1210 leukaemia treated with combinations of adriamycin with cyclophosphamide, isophosphamide with acetylcysteine and methotrexate with leucovorin. Two established DSM (Nelder-Mead and Box) were used, and a new method was designed to find consistent search paths in spite of wide biological variation. With methotrexate and leucovorin, DSM located combinations prolonging mean survival to 40-50 days (compared with 10.4 in controls) and giving high proportions of long-term survivors. These results were achieved with single injections of drugs given 7 days after injection of 10(6) leukaemic cells, i.e. 2-3 days before deaths began in untreated mice, and appear to be unprecedented with these agents. Searching for optimal combinations of established agents may be at least as rewarding as searching for new agents, and thus DSM may prove a powerful tool for improving the results of combination cancer chemotherapy.
Four new hydroporphyrins [the o, m and p isomers of 5,10,15,20-tetra(hydroxyphenyl)chlorin and 5,10,15,20-tetra(m-hydroxyphenyl)bacteriochlorin] related to the tetra(hydroxyphenyl)porphyrins have been prepared. They show the expected strong absorption bands in the red region of the visible spectrum and are found to be very effective tumour photosensitizers.
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Explore the source record for details and available documents.
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Exposure of the cranium to white light in mice that had been given haematoporphyrin derivative (HpD) led to a rapid onset of vasogenic cerebral oedema, cerebral necrosis, coma and death. Selectivity of the initial damage for endothelium was suggested by (a) early breakdown (less than 1 h) of the blood-brain barrier (BBB) as shown by increased permeability to Evans blue (b) separation and increased vesiculation of endothelial cells at 2 h and (c) endothelial cell pyknosis at 3--4 h in small vessels next to apparently undamaged neurones and neuroglia. There was no damage to myelin sheaths, and astrocytes showed only end-feet oedema, a reaction to exudation of protein-rich fluid. Within a few hours of illumination, most cells in the illuminated area were necrotic. Cerebral photosensitivity persisted for at least 12 weeks after a single injection of HpD. Our results suggest that the primary site of damage in the brain is the endothelium of small vessels, and that HpD remains associated with this for a remarkably long time. These findings are relevant to the mechanisms by which photodynamic therapy damages other tissues, including neoplasms, and particularly to the possible application of this treatment to brain tumours.
We compared para-, meta- and ortho-isomers of meso-tetra(hydroxyphenyl)porphyrin (p-, m- and o-THPP) and the potassium salt of the para compound (K-p-THPP) with haematoporphyrin derivative (HpD) and Photofrin II in their ability to sensitise tumours, skin and brain to light. HpD and Photofrin II induced modest tumour photosensitisation at the cost of substantial skin and brain sensitisation. At doses low enough to keep sensitisation of these normal tissues within acceptable limits, tumour sensitisation was sufficient to give necrosis only approximately 2 mm deep after exposure to 10 J cm-2 light. In contrast, doses of p-THPP, K-p-THPP and m-THPP that produced skin and brain sensitivity within acceptable limits sensitised tumours enough to give 4-9 mm necrosis after 10 J cm-2 light. m-THPP was, on a molar basis, about 25-30 times as potent as HpD and Photofrin II in sensitising tumours. o-THPP was also a potent tumour photosensitiser, but induced a prohibitive degree of skin photosensitivity even at low doses. It is unlikely that these differences in relative selectivity are due to differences in such photophysical parameters as optimum activating wavelength (which would affect tissue penetration by light), or light absorption, and physicochemical factors that determine tissue localisation may be involved. The high tumour sensitising potency and favourable tissue selectivity of m-THPP, p-THPP and K-p-THPP make them promising candidates for clinical tumour phototherapy.