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Biomedical subjects

S H Selman

Publications and source records attributed to S H Selman.

At least 37 records · Page 2Linked to original sources
PubMed1994

Photodynamic therapy of tumors: effects of hematoporphyrin derivative on normal rat intestine.

Hematoporphyrin derivative (HpD) is a complex mixture of dicarboxylic porphyrins in addition to dimers, oligomers and aggregates of variable sizes. The ability of this mixture (and enriched preparations thereof) to be retained by tumors and to sensitize them to destruction by light has led to worldwide studies of the treatment modality called photodynamic therapy (PDT). Understanding how PDT affects normal tissues surrounding the tumor is of crucial importance. Prior studies have documented that normal intestinal blood flow can be disrupted by HpD PDT. In addition, mucosal and submucosal damage to normal rat jejunum was observed following HpD PDT. The present study was designed to correlate the above observed changes with local levels of porphyrins. Three groups of Fischer 344 rats were injected with 0 (controls), 10 or 20 mg HpD/kg body weight. Twenty-four hours after the drug was injected, jejunal segments were excised and blood samples taken. Jejunal contents were obtained by saline perfusion and analyzed for porphyrins alongside the jejunal homogenates and the bloods. Jejunal segments of animals injected with 10 or 20 mg HpD/kg b.w. had porphyrin levels some 4- and 9-fold above controls (controls m +/- S.D. = 0.25 +/- 0.12 micrograms/g wet weight). For each injected dose the jejunal perfusates contained 2- and 3-fold higher levels of porphyrins (in transit) as the controls (controls, m +/- S.D. = 1.48 +/- 0.66 micrograms/g w.w.). In the general circulation, only 0.6% or 0.4% of the respective injected doses remained. After HpD i.v. injections, high levels of porphyrins were found in the small intestine and in transit.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Enhanced skin allograft survival after photodynamic therapy. Association with lymphocyte inactivation and macrophage stimulation.

It has been found previously that peritoneal exposure to hematoporphyrin derivative (HpD) photodynamic therapy (PDT) can induce systemic immunosuppression of contact hypersensitivity. We have now found that HpD-PDT also significantly prolongs survival of murine skin allografts. Normal A/J mice transplanted with BALB/c skin rejected the grafts within 10 +/- 0.9 days. Recipient mice treated 24 hr previously with HpD-PDT rejected skin allografts at 16 +/- 1.2 days. HpD alone or irradiation alone had no effect on skin graft survival, nor did HpD-PDT administered shortly after grafting. Flow cytometric analyses showed a nearly complete depletion of peritoneal lymphocytes 3 days after HpD-PDT. Lymphocyte levels were normal in the spleen, an organ not directly targeted by the PDT treatment, but the cells were totally unresponsive to Con A and LPS mitogens. Conversely, peritoneal HpD-PDT caused a striking enhancement in macrophage function as measured by phagocytosis of antibody-coated sheep erythrocytes. Humoral immunity to hen egg-white lysozyme was not significantly changed by HpD-PDT. These results demonstrate that HpD-PDT causes systemic immunosuppression of cellular immunity which, in turn, allows prolonged survival of allografts. Humoral immunity appears to remain largely unaffected by HpD-PDT and macrophages become activated, suggesting that this therapy might be more effective in specifically targeting T cell-mediated immunity than current immunosuppressive treatments.

Animals↗
PubMed1993

Copper benzochlorin, a novel photosensitizer for photodynamic therapy: effects on a transplantable urothelial tumor.

An iminium salt of octaethylbenzochlorin with copper in the aromatic ring, CDS1, was tested for its tumoricidal effects on the AY-27 N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide tumor line. CDS1 was found to be an effective photosensitizer in vivo when used in combination with either a xenon arc lamp or a pulsed alexandrite laser. Hemodynamically, CDS1 and light caused a rapid decrease in tumor blood flow. Skin photosensitization was found to be minimal when drug-injected mice were illuminated in a solar simulator.

Animals↗
PubMed1993

Iminium salt of copper benzochlorin (CDS1), a novel photosensitizer for photodynamic therapy: mechanism of cell killing.

The mechanism of cell killing by CDS1, an iminium salt of octaethylbenzochlorin with copper in the aromatic ring, in combination with light from a noncoherent light source was investigated. Using a standard clonogenic assay and the AY-27 FANFT tumor line, photoactivation of CDS1 was shown to be cytotoxic. The photodynamic cell killing ability of CDS1 required the presence of molecular oxygen. The reactive species generated by light activation of CDS1 were effectively quenched by N,N'-diphenyl-p-phenylenediamine. Additionally, the photodynamic effect of CDS1 was not enhanced by deuterium oxide. To characterize the reactive oxygen species generated by the photoactivation of CDS1 the well-characterized erythrocyte ghost model was used. Superoxide dismutase and catalase were potent inhibitors of CDS1-induced lipid peroxidation of erythrocyte membranes. Sodium azide only partially inhibited lipid peroxidation. These findings differed from the known singlet oxygen generator, tin (II) etiopurpurin dichloride (SnET2). Sodium azide was a potent inhibitor of SnET2-induced lipid peroxidation, whereas superoxide dismutase and catalase were totally ineffective. Based on these results, we conclude that CDS1 requires the presence of molecular oxygen for cell killing to occur but appears to act primarily through a non-singlet oxygen mechanism.

Animals↗
PubMed1993

Massive necrotizing pancreatitis in an immunosuppressed renal transplant recipient (successful therapy).

Severe pancreatitis may be associated with massive necrosis of the pancreas and/or retroperitoneal adipose tissue. Toxicity results from the dead tissue and secondary infection. A 45 year old patient, while fully immunosuppressed, developed this complication following cadaveric renal transplantation. He survived continued immunosuppression, 16 operative debridements of the retroperitoneum, and maintained a functioning renal transplant. In view of the previously reported high mortality rates from mild pancreatitis after transplantation, the current experience warrants further evaluation of the open method of treatment.

Acute Disease↗
PubMed1992

A new technique for bladder washing.

We describe a simple adaptation of the Water Pik (Teledyne Water Pik, Fort Collins, Colorado) irrigating device which allows vigorous, direct-vision agitation of the bladder wall. Three groups of mongrel dogs were subjected to cystoscopy and either syringe barbotage, half-speed Water Pik irrigation, or full-speed Water Pik irrigation of the bladder wall. Transitional cell counts were then done on centrifuged aliquots of each bladder wash specimen. The average number of transitional cells per high-power field were similar between the control group and the syringe barbotage group (2.5 and 1.5 respectively). However, both the half-speed and the full-speed Water Pik groups demonstrated statistically higher cell counts (5.7 and 13.7) when compared to both the controls and syringe barbotage groups. We conclude that Water Pik irrigation is an effective method to increase cell yield in bladder wash specimens.

Animals↗
PubMed1992

Mechanisms of cell killing in photodynamic therapy using a novel in vivo drug/in vitro light culture system.

Photodynamic therapy of certain neoplasms has emerged as a promising form of cancer treatment. This type of therapy involves the exogenous administration of a photosensitizer with subsequent exposure to light. The ensuing photochemical reaction results in destruction of the tumor. Whether tumor cells are destroyed directly by the photodynamic treatment or indirectly as a result of destruction of the tumor microvascular bed is unknown. To address this question, methods were adapted to test whether combinations of a photosensitizer and light resulted in direct cell killing of precision cut tissue slices placed in culture. The major advantages of this culture system are that photosensitizers are administered in vivo, tissue slices produced in minutes, placed in culture medium, and irradiated in vitro. Any resulting cellular destruction occurs in the absence of a functioning vascular system and indicates that photodynamic therapy acts through a direct cell killing mechanism. Tissue slice viability was monitored by two standard methods: assay for intracellular potassium and morphological examination at the electron microscopic level. The effects of hematoporphyrin derivative and light were examined on tissue slices produced from a prostate adenocarcinoma transplanted into male Copenhagen rats. The data indicate that direct killing of tumor slices occurs and is dependent on the irradiation protocol used.

Animals↗
PubMed1992

Observations on the synthesis and in vivo photodynamic activity of some benzochlorins.

An improved synthesis of benzochlorins is reported. Demetallation of the meso-hydroxymethylvinyl derivative of octaethylporphyrin, followed by treatment with sulfuric acid results in cyclization to generate the corresponding octaethylbenzochlorin in high yield. Prolonged treatment with acid generates the sulfonated derivative. These sensitizers were shown to be efficient photodynamic agents in vivo. Animals bearing a transplanted N-[4-(5-nitro-2-furyl)-2-thiazoly]formamide induced urothelial tumor were treated with either the benzochlorin or its sulfonated derivative. Irradiation of tumors 24 h later resulted in a significant tumoricidal effect in a short term assay. We conclude that benzochlorins warrant further examination as potential agents for use in photodynamic therapy.

Animals↗
PubMed1991

Synthesis and in vivo photodynamic activity of some bacteriochlorin derivatives against bladder tumors in rodents.

Bacteriochlorins have been suggested as potential photosensitizers for use in photodynamic therapy. We have shown that bacteriochlorin-like macrocycles can be generated through cyclization of either 5,10- or 5,15-bis[(ethoxycarbonyl)vinyl]porphyrins; however, the resulting products are rapidly decomposed on exposure to air. More stable systems can be generated by Diels-Alder reactions between dienophiles such as dimethyl acetylenedicarboxylate or tetracyanoethylene, and vinylporphyrinones. Although spectroscopic properties of these latter products resemble those of porphyrinones rather than bacteriochlorins, in vivo studies using the N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide-induced rat bladder tumor (AY-27) transplanted into Fisher CDF (F344)/CrlBr rats demonstrated a powerful photodynamic response.

Animals↗
PubMed1991

Photodynamic therapy: effect on the endothelial cell of the rat aorta.

Previous studies in our laboratory have demonstrated that photodynamic therapy (PDT) of experimental bladder tumors leads to rapid destruction of the endothelial lining within the tumor microvasculature. Endothelial cell death during PDT may be a consequence of direct cell injury resulting from retention of photosensitizer within the endothelial cell or, alternatively, result from intravascular activation of circulating photosensitizer with subsequent indirect endothelial damage. In the experiments described here, we investigated the possibility that photosensitizer retained within the endothelial cell was sufficient to cause endothelial cell injury in the absence of circulating drug. The experimental model was rat aorta photosensitized in vivo via the intravenous injection of tin(II) etiopurpurin dichloride (SnET2), and subsequent in situ or in vitro (in explant culture) light (670 nm) treatment from an argon pumped dye laser. Damage to the lining of the aorta was assessed morphometrically by determining the areal density of silver stained endothelial cells. Results indicate that purpurin SnET2-PDT directly damages the endothelial lining.

Animals↗
PubMed1991

Treatment of the transplantable FANFT induced bladder tumors with the purpurin SnET2 and red light emitted by a pulsed frequency doubled Nd:YAG laser.

Photodynamic therapy of transplantable N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide-induced tumors engrafted onto Fischer CDF (F-344)/CrlBR rats that had been sensitized with the photosensitizer tin (ll) etiopurpurin dichloride was performed in combination with visible light (approximately equal to 660 nm) emitted by either a continuous wave argon-dye laser or a pulsed, frequency-doubled Nd:Yag laser. Tumor control was assessed either by tumor dry-weight 12 days after treatment or by the palpatory absence of tumor at 60 days after treatment. Both laser sources were effective in creating the desired photodynamic effect. This study demonstrates the potential for the use of a solid-state pulsed laser for photodynamic therapy when used in combination with the tumor sensitizer tin (ll) etiopurpurin dichloride.

Animals↗
PubMed1990

Hemodynamic effect of the metallopurpurin SnET2 and light on transplantable FANFT induced bladder tumor.

Changes in blood flow to transplantable N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide induced bladder tumors growing subcutaneously in the flanks of Fischer CDF (F344/CrlBR) rats were measured after photodynamic therapy with the photosensitizer tin (II) etiopurpurin dichloride using the radioactive microsphere technique. As with the other photosensitizers, hematoporphyrin derivative and chloroaluminum tetrasulfophtalocyanine, tin (II) etiopurpurin dichloride and light caused a rapid decrease in tumor blood flow in this tumor model. The decrease in blood flow occurred whether the vehicle for photosensitizer delivery was an emulsion or a liposome. Systemic heparinization of animals prior to light treatment did not alter changes in tumor blood flow.

Animals↗
PubMed1990

Diels-Alder adducts of vinyl porphyrins: synthesis and in vivo photodynamic effect against a rat bladder tumor.

Benzoporphyrin derivatives have been proposed as potential photosensitizers for photodynamic therapy. We have prepared a number of benzoporphyrin derivatives and tested their effect, in combination with red light, on the N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) induced rat bladder tumor (AY-27) transplanted into Fischer CDF(F344)/CrlBr rats. Tetracyanoethylene (TCNE) adducts showed very little activity, which may be attributable to their poor tumor uptake or to chemical instability of the adduct under physiological conditions. However, dimethyl acetylenedicarboxylate (DMAD) adducts tested showed greater cytotoxic effect than hematoporphyrin derivative and similar activities to metallopurpurins when tested under the same protocol.

Acetylene↗