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B W Henderson

Publications and source records attributed to B W Henderson.

17 recordsLinked to original sources
PubMed1992

Implications of a pre-existing tumor hypoxic fraction on photodynamic therapy.

The presence of oxygen in tissue is a requirement for photodynamic therapy (PDT)-induced destruction of solid tumors, otherwise no cell death occurs. Since many tumors have been shown to have significant populations of hypoxic cells, it is of clinical interest to determine if pre-existing tumor hypoxia limits phototherapy. This question was examined using RIF tumors where tumor response to PDT of completely oxygenated tumors was compared to tumors with an induced hypoxic fraction. Tumor hypoxia was induced by using vasoactive drugs (epinephrine, chlorpromazine, or isoproterenol), given 30 min prior to PDT, or by a surgical method. PDT consisted of 5 mg/kg Photofrin II ip 24 hr prior to treatment and 135 J/cm2 630-nm light. The administration of the various vasoactive agents induced hypoxic fractions of 2.2 to 10%. The surgical method induced hypoxic fractions of 35%. Tumor response and cure in animals given vasoactive agents did not differ from controls, suggesting that low levels of pre-existing tumor hypoxia do not limit photodynamic therapy in this tumor model. Animals with tumors made hypoxic by a surgical method showed significantly reduced tumor response to PDT. Only 14% of these animals had tumors which became flat and necrotic by the day following PDT, compared to nearly 100% for animals given vasoactive drugs or controls. Furthermore, no tumor cure was observed in animals treated by this method. The higher level of tumor hypoxia in these animals likely represents one point where large proportions of PDT-resistant cells can survive after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effects of photodynamic treatment of platelets or endothelial cells in vitro on platelet aggregation.

The purpose of this work was to gain insight into the role played by platelets and endothelial cells in the development of thrombogenic vascular events, observed after in vivo photodynamic therapy (PDT), by studying the in vitro effects of PDT on isolated human platelets and cultured human and bovine endothelial cells. Exposure to Photofrin II (PII) and light caused platelets to rapidly lose their ability to aggregate. Photofrin II alone at high concentrations also exerted inhibitory effects on aggregation. Endothelial cells exposed to PII- and phthalocyanine (GaCl-PcS2,3 or Zn-PCS1,2)-mediated PDT released potent platelet anti- and disaggregating activity which could be identified as prostacyclin by the following criteria: a close correlation between the time and dose dependent anti-aggregating effects and released 6-keto-PGF1 alpha (the spontaneous hydrolysis product of PGI2, determined by radioimmunoassay), the inhibition of these effects by indomethacin, accumulation of 6-keto-PGF1 alpha metabolite in the media of cells treated with PDT (as determined by HPLC analysis), and the absence of evidence for significant nitric oxide production. This prostacyclin release occurred following plasma membrane damage. Although no pro-aggregating activity was observed, endothelial cells were found to release considerable amounts of arachidonic acid and prostaglandin F2 alpha in response to PDT. These data, which indicate powerful anti-thrombogenic effects in vitro, are in sharp contrast to the vascular effects of PDT in vivo which are characterized by severe platelet aggregation, and imply that the in vivo effects involve additional components of the vascular system.

Adenosine Triphosphate↗
PubMed1991

Bacteriochlorophyll-a as photosensitizer for photodynamic treatment of transplantable murine tumors.

Bacteriochlorophyll-a (bChla), which absorbs light of 780 nm wavelength, was tested for in vivo photodynamic activity in the SMT-F and RIF transplantable mouse tumor systems. High performance liquid chromatography (HPLC) analysis of tissue extracts showed that bChla was rapidly degraded in vivo to bacteriopheophytin-a (bPheoa) and other breakdown products. These were also photodynamically active, and tumor response could be achieved over a wavelength range of 660 to 780 nm, while tumor cure was restricted to wavelengths of 755 (bPheoa) to 780 nm. A photosensitizing product absorbing at 660 nm was also present in isolated tumor cells. Photodynamic cell kill of tumor cells isolated from tumors after bChla accumulation in vivo, using 775 or 780 nm light in vitro, was exponential up to 20-40 J cm-2. Above this light dose little or no further damage could be achieved, which is an indication of the rapid photobleaching of these sensitizers. In vivo, vascular occlusion occurred readily if light treatment was delivered shortly after sensitizer administration, but was delayed if light treatment was carried out 24 h after injection. Although up to 70% of tumor cells were lethally damaged after completion of in vivo light treatment, concurrent severe vascular destruction seemed necessary for tumor cure. Normal tissue photosensitivity totally subsided within 5 days after sensitizer administration.

Animals↗
PubMed1989

Release of prostaglandin E2 from cells by photodynamic treatment in vitro.

Photodynamic treatment in vitro, using the photosensitizer Photofrin II and light at 630 nm, was found to liberate large amounts of prostaglandin E2 (PGE2) from mouse radiation-induced fibrosarcoma tumor cells and peritoneal macrophages, but not from L929 fibroblasts. PGE2 release was dose dependent and directly related to cell membrane disruption. It occurred rapidly and was complete within 30 min of treatment. PGE2 release could be inhibited by indomethacin, meclofenamate and extended prior exposure to dexamethasone, indicating that it was due to new production involving both the phospholipase and cyclooxygenase enzyme systems. Removal of calcium ions, necessary for phospholipase activation, from the medium did not inhibit the photodynamically induced elevated PGE2 production, possibly because of Ca2+ resupply from leaking intracellular pools.

Animals↗
PubMed1989

Tissue localization of photosensitizers and the mechanism of photodynamic tissue destruction.

This paper outlines our present knowledge of photosensitizer tissue distribution, derived from preclinical animal studies, and relates it to the observed biological response to photodynamic therapy (PDT). Emphasis is placed on porphyrins (haematoporphyrin derivative (HpD), Photofrin II) and phthalocyanines (aluminum phthalocyanine sulphonate AlPcS). In mice, both groups of sensitizers show multiphasic plasma clearance kinetics with an initial rapid decline followed by further slow reduction. Residual amounts of Photofrin II are detectable 75 days after injection. Drug elimination occurs through urine and faeces, but faecal elimination predominates for Photofrin II. Circulating sensitizer greatly influences the mouse ear-swelling response, but not the foot response. Tumours and normal skin can be destroyed by vascular damage, if illumination occurs at times of maximal plasma sensitizer concentration, with no detectable sensitizer accumulation in tumour cells. Organ retention for both photosensitizer groups is similar and persistent. Organs rich in reticuloendothelial elements (liver, kidney, spleen) accumulate and retain the highest levels, skin and muscle the lowest, while normal brain tissue excludes sensitizer. The adrenal and pancreatic glands, as well as urinary bladder, also retain high amounts of Photofrin II. Tumour/skin ratios of 1 to 3:1 and 2 to 7:1 have been reported for porphyrins and sulphonated phthalocyanines respectively. Tissue destruction upon light exposure is not always correlated with photosensitizer levels, as is exemplified by liver and pancreas. Stromal sensitizer localization usually predominates in tumour and normal tissue, and often determines tumour response. Certain compounds, such as monosulphonated tetraphenylporphyrin and AlPcS, may favour parenchymal localization. The formed blood elements remain free of photosensitizer, while mast cells and macrophages accumulate especially large amounts and, upon illumination, release an array of vasoactive inflammatory and immune mediators.

Animals↗
PubMed1989

Oxygen limitation of direct tumor cell kill during photodynamic treatment of a murine tumor model.

The relationship between levels of in vivo accumulated photosensitizer (Photofrin II), photodynamic cell inactivation upon in vitro or in vivo illumination, and changing tumor oxygenation was studied in the radiation-induced fibrosarcoma (RIF) mouse tumor model. In vivo porphyrin uptake by tumor cells was assessed by using 14C-labeled photosensitizer, and found to be linear with injected photosensitizer dose over a range of 10 to 100 mg/kg. Cellular photosensitivity upon exposure in vitro to 630 nm light also varied linearly with in vivo accumulated photosensitizer levels in the range of 25 to 100 mg/kg injected Photofrin II, but was reduced at 10 mg/kg. Insignificant increases in direct photodynamic cell inactivation were observed following in vivo light exposure (135 J/cm2, 630 nm) with increasing cellular porphyrin levels. These data were inconsistent with expected results based on in vitro studies. Assessment of vascular occlusion and hypoxic cell fractions following photodynamic tumor treatment showed the development of significant tumor hypoxia, particularly at 50 and 100 mg/kg of Photofrin II, following very brief light exposures (1 min, 4.5 J/cm2). The mean hyupoxic cell fractions of 25 to 30% in these tumors corresponded closely with the surviving cell fractions found after tumor treatment in vivo, indicating that these hypoxic cells had been protected from PDT damage. Inoculation of tumor cells, isolated from tumors after porphyrin exposure, into porphyrin-free hosts, followed by in vivo external light treatment, resulted in tumor control in the absence of vascular tumor bed effects at high photosensitizer doses only.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Photodynamic therapy--coming of age.

With the advent of Phase III clinical trials, photodynamic therapy of solid tumors is about to gain respectability within the field of cancer therapy. This treatment modality uses visible light to activate tumor-localizing photosensitizers, and causes tissue destruction by generating highly cytotoxic molecular oxygen species. The almost universal tumor response achievable, mild general toxicity, and repeatability of treatment without loss of effectiveness account for its application in a wide variety of human neoplasms. A decade of basic and preclinical research has laid a solid foundation of knowledge of the mechanisms of the photodynamic effect, both on the cellular and tissue levels. Although open questions remain, these efforts have provided the rationale for new directions of development, such as the design of new photosensitizers and improved light sources. This report describes the events involved in photodynamic tumor destruction, emphasizing possible ways to improve this therapy in the future.

Cell Survival↗
PubMed1988

Modification of photodynamic therapy-induced hypoxia by fluosol-DA (20%) and carbogen breathing in mice.

The administration of a perfluorochemical emulsion and carbogen (95% O2, 5% CO2) breathing before photodynamic therapy (PDT) was studied to determine how increased levels of tumor oxygenation may affect PDT-induced tumor destruction. C3H/HeJ mice bearing the RIF tumor were given injections of 5 to 10 mg/kg of dihematoporphyrin ethers 24 h prior to treatment. Animals were given injections of 12 ml/kg of Fluosol-DA (20%) followed by carbogen breathing or 12 ml/kg of saline and air breathing (controls) 1 h before tumors were exposed to 135 J/cm2 of 630-nm light treatment. Changes in the hypoxic fraction of tumors, the time course for decreases in tumor cell clonogenicity, and tumor response were measured immediately and at various times after treatment. The administration of Fluosol-DA (20%) and carbogen breathing was found to delay the onset of PDT-induced hypoxia through the first hour posttreatment. Progressive tumor hypoxia was observed after 4 h posttreatment. The time period in which tumors remained well oxygenated coincided with observations of increased tumor cell survival. Decreases in tumor cell clonogenicity were observed only after tumor cells became hypoxic. These findings were consistent with the 24-h delay in complete tumor response in animals given Fluosol-DA (20%) and carbogen breathing before PDT. There were only minor variations in long-term tumor response and cure observed between the two groups tested. A second series of experiments was done to assess any treatment advantage of the adjuvant use of Fluosol-DA (20%) and carbogen breathing with PDT at high tumor photosensitizer levels. At an injected dose of 50 mg/kg of dihematoporphyrin ethers, no such advantage was observed. The administration of Fluosol-DA (20%) and carbogen breathing did not reduce the extent of PDT-induced microvascular damage, maintain high levels of tumor oxygenation through light treatment, or modify the extent of tumor cell kill following treatment.

Animals↗
PubMed1987

Relationship of tumor hypoxia and response to photodynamic treatment in an experimental mouse tumor.

The relationship between tumor oxygenation and the effectiveness of photodynamic therapy (PDT) was studied in vitro and in vivo using the RIF mouse tumor model. The oxygen dependence of photodynamic inactivation of RIF cells, which had been exposed to 25 mg/kg porphyrin (dihematoporphyrin ether) in vivo, isolated and illuminated in vitro, was determined. No cell kill was achieved under anoxic conditions, full effect was reached at 5% O2, and the half value of cell inactivation was found to be at 1% O2. Tumor hypoxia was assessed after in vivo gamma-irradiation of control and PDT-treated tumors by in vitro clonogenic assay of cell radiosensitivity. In vitro control experiments established that the radio-sensitivity of PDT-surviving RIF cells was identical to that of untreated control cells. RIF tumors of treatment size (80-120 mg) contained no detectable hypoxic tumor cell fraction. PDT treatment consisting of i.p. injection of 10 mg/kg dihematoporphyrin ether 24 h prior to 45 J/cm2 of 630 nm light, rendered approximately 9% of tumor cells severely hypoxic within 10 min of treatment time. An illumination period of 30 min (135 J/cm2) induced a hypoxic tumor cell fraction of 17%, which increased to 47% within 1 h posttreatment. Despite the prompt induction of tumor hypoxia during PDT light treatment, the tumors proved highly curable (81% cures) under the present treatment conditions (depilation of tumor area, 10 mg/kg dihematoporphyrin ether i.p., 135 J/cm2). Considering the reduced effectiveness of photodynamic cell kill at low oxygen concentrations, the rapid induction of tumor hypoxia by PDT itself, and the high tumor cure rate, it has to be concluded that in the RIF tumor hypoxic tumor cells are inactivated by a mechanism other than direct photodynamic cytotoxicity, and are thus not limiting to PDT tumor response.

Animals↗
PubMed1987

Hyperthermic potentiation of photodynamic therapy employing Photofrin I and II: comparison of results using three animal tumor models.

Hyperthermia induced by a microwave source (2,450 MHz) was used alone and in combination with photodynamic therapy (PDT) to treat the SMT-F, EMT-6, and RIF animal tumors in vivo. PDT was administered using either Photofrin I or II as the photosensitizer and an argon-pumped tunable dye laser (630 nm) as the light source. Greater than additive increases in long-term tumor control were achieved when hyperthermia was given immediately post-PDT in the SMT-F and RIF tumor systems. Only additive (or independent) increases in tumor control were achieved when hyperthermia was given immediately before PDT in all these tumor systems and when heat was applied post-PDT using the EMT-6 tumor. In a series of experiments using the SMT-F tumor, it was observed that decreases in PDT drug or light doses could be offset (in terms of tumor control) by the addition of a subsequent heat treatment. This result, along with others presented, indicates the clinical potential of PDT and hyperthermia as adjuvant cancer modalities.

Animals↗
PubMed1986

The influence of cellular glutathione content on cell survival following photodynamic treatment in vitro.

The influence of cellular glutathione (GSH) levels on the response to photodynamic treatment (PDT) in vitro was determined in cells which either were depleted of GSH by buthionine sulfoximine (BSO) or were genetically GSH deficient. The effects of GSH depletion on cellular radiosensitivity were studied in parallel for the purpose of comparison. BSO treatments which reduced GSH levels in four cell lines (CHO, V79, EMT6, RIF) to approximately 80% of controls, 30% of controls, or undetectable levels uniformly decreased cell survival. This decrease was directly related to GSH depletion levels and was expressed mainly in a reduction of the width of the survival curve shoulder (Dq). GSH level-dependent aerobic radiosensitization following BSO treatment was likewise found in all four cell lines. In contrast to PDT, however, cell survival changes were expressed in the dose slopes (Do's) of the survival curves. Cell survival of GSH-deficient human fibroblasts (GM 3877) was decreased following PDT and gamma irradiation when compared to their normal counterparts (GM 5659). In both modalities the difference was mainly due to a reduction in the Dq's, while the Do's were only slightly affected. The augmented response to PDT was not caused by interference by BSO or GSH with either cellular porphyrin uptake or singlet oxygen production during the photodynamic process. Possible mechanisms of GSH effects on PDT were discussed.

Animals↗
PubMed1986

Effects of scavengers of reactive oxygen and radical species on cell survival following photodynamic treatment in vitro: comparison to ionizing radiation.

The effects of various scavengers of reactive oxygen and/or radical species on cell survival in vitro of EMT6 and CHO cells following photodynamic therapy (PDT) or gamma irradiation were compared. None of the agents used exhibited major direct cytotoxicity. Likewise, none interfered with cellular porphyrin uptake, and none except tryptophan altered singlet oxygen production during porphyrin illumination. The radioprotector cysteamine (MEA) was equally effective in reducing cell damage in both modalities. In part, this protection seems to have been induced by oxygen consumption in the system due to MEA autoxidation under formation of H2O2. The addition of catalase, which prevents H2O2 buildup, reduced the effect of MEA to the same extent in both treatments. Whether the remaining protection was due to MEA's radical-reducing action or some remaining oxygen limitation is unclear. The protective action of MEA was not mediated by a doubling of cellular glutathione levels, since addition of buthionine sulfoximine, which prevented glutathione increase, did not diminish the observed MEA protection. The hydroxyl radical scavenger mannitol also afforded protection in both kinds of treatment, but it was approximately twice as effective in gamma irradiation as in PDT. This is consistent with the predominant role of OH radicals in ionizing radiation damage and their presumed minor involvement in PDT damage. Superoxide dismutase, a scavenger of O2, acted as a radiation protector but was not significantly effective in PDT. Catalase, which scavenges H2O2, was ineffective in both modalities. Tryptophan, an efficient singlet oxygen scavenger, reduced cell death through PDT by several orders of magnitude while being totally ineffective in gamma irradiation. These data reaffirm the predominant role of 1O2 in the photodynamic cell killing but also indicate some involvement of free radical species.

Animals↗
PubMed1986

Effect of DL-buthionine-S,R-sulfoximine on the growth of EMT6 and RIF mouse tumors.

The response of murine EMT6 and RIF tumors to DL-buthionine-S, R-sulfoximine (BSO), a glutathione (GSH) depletor, given either as a single dose, continuous oral administration, or in multiple doses, was determined with the use of a tumor-growth-delay assay. BSO consistently caused significant tumor growth delay in EMT6 tumors, which reached 5-7 days (two doubling times) after a single BSO dose (40 mumol/kg or 4 mmol/kg), 3 days (one doubling time) with continuous oral administration (20 mM), and 9 days (three doubling times) with daily BSO administrations (4 mmol/kg) starting at the time of tumor inoculation. Growth inhibition persisted after discontinuation of BSO treatment. Some complete tumor regressions were observed. Only slight tumor growth delay (one doubling time) was observed in RIF tumors at all treatment modes. No direct correlation was observed between tumor GSH content and the effects on tumor growth. In vitro BSO pretreatment (2 mM, 24 hr) of EMT6 tumor cells prior to tumor inoculation, which reduced cellular GSH levels to 34% of controls, did not influence subsequent tumor growth. Pretreatment of mice with BSO (4 mmol/kg, 1 daily sc injection for 7 days) prior to tumor inoculation led to a reduction of tumor takes by 25% when compared to 100% tumor takes in untreated mice. These data imply a BSO-induced change in the host response to tumor development.

Animals↗
PubMed1985

Potentiation of photodynamic therapy by heat: effect of sequence and time interval between treatments in vivo.

Photodynamic therapy (PDT) utilizing hematoporphyrin derivative (Hpd) as photosensitizer and an argon-dye laser as the light source was used alone and in combination with a localized microwave hyperthermia treatment to treat the SMT-F mammary carcinoma in mice. A 30-min heat treatment at 44.5 degrees C was applied 0-8 hr before or after a standard photodynamic treatment (67.5 or 135 J/cm2, given 24 hr post-7.5 mg/kg Hpd). Potentiation of PDT by heat was found to be related to the sequence of the treatments and the time interval between them. When 44.5 degrees C for 30 min was applied immediately after a 15-min PDT treatment, significant potentiation was seen (58% long-term tumor control vs 3 and 10%, respectively, for PDT and heat alone). This potentiation decreased with increasing time between PDT and heat, with tumor control values decreasing to 36, 20, and 14%, when 2, 4, and 8 hr, respectively, were allowed between treatments. Only additive effects of the independent therapies were found when this heat treatment was applied 0-8 hr before PDT. In other experiments, mice were treated with single or fractionated 30-min PDT treatments (two 15-min treatments separated by 0-, 2-, 4- or 8-hr intervals). Decreases in tumor control were seen with increasing time interval; only minor differences in tumor control were seen when 4-8 hr was allowed between treatments compared to a single 15-min treatment.

Animals↗