Immunosuppressive effects of silicon phthalocyanine photodynamic therapy.

The purpose of this study was to determine if silicon phthalocyanine 4 (Pc 4), a second-generation photosensitizer being evaluated for the photodynamic therapy (PDT) of solid tumors, was immunosuppressive. Mice treated with Pc 4 PDT 3 days before dinitrofluorobenzene sensitization showed significant suppression of their cell-mediated immune response when compared to mice that were not exposed to PDT. The response was dose dependent, required both Pc 4 and light and occurred at a skin site remote from that exposed to the laser. The immunosuppression could not be reversed by in vivo pre-treatment of mice with antibodies to tumor necrosis factor-alpha or interleukin-10. These results provide evidence that induction of cell-mediated immunity is suppressed after Pc 4 PDT. Strategies that prevent PDT-mediated immunosuppression may therefore enhance the efficacy of this therapeutic modality.

A comparative analysis of silicon phthalocyanine photosensitizers for in vivo photodynamic therapy of RIF-1 tumors in C3H mice.

Photofrin photodynamic therapy (PDT) has recently received FDA approval for the palliative treatment of totally and partially obstructing esophageal malignancies. However, there is a need for new PDT photosensitizers because Photofrin has a number of undesirable features. The purpose of this study was to evaluate the efficacy of four amine-bearing silicon phthalocyanines--Pc4, Pc10, Pc12 and Pc18--as potential PDT photosensitizers. Equimolar concentrations of these Pc were found to be highly effective at causing the regression of RIF-1 tumors transplanted to C3H/HeN mice. The amount of Pc4 necessary to cause an equivalent amount of tumor regression in this model system was substantially less than the amount of Photofrin. The cutaneous phototoxicity of the silicon Pc photosensitizer was assessed by the utilization of the murine ear-swelling model. When C3H mice were exposed to 167 J/cm2 of polychromatic visible light from a UVB-filtered solar simulator, which emitted UV radiation and visible light above 320 nm, the Pc produced little, if any, cutaneous photosensitivity. These results indicate that Pc4, Pc10, Pc12 and Pc18 are at least as effective as Photofrin in PDT protocols, while at the same time addressing many of the drawbacks of Photofrin.

Genetic variation in low-dose UV-induced suppression of contact hypersensitivity and in the skin photocarcinogenesis response.

Two of the major cutaneous consequences of ultraviolet (UV) radiation exposure are immunosuppression and the development of skin cancer. This study examined whether these effects are genetically determined. Suppression of contact hypersensitivity by local, low-dose UV radiation was examined in what have been termed "UV-susceptible" and "UV-resistant" strains of mice. C3H/HeJ mice ("UV resistant") were resistant to the adverse effects of low-dose UV radiation when normal doses of hapten were applied to UV-irradiated skin; however, they were sensitive when the amount of hapten used for sensitization was reduced. A similar effect was observed in BALB/c mice ("UV resistant") and when the hapten was dimethylbenz(a)anthracene, thus indicating that the genetic variation was not strain or hapten specific. Despite the fact that some strains were sensitive and some were resistant to low-dose UV radiation when high doses of hapten were employed, all strains initially sensitized to hapten through UV-irradiated skin were found to be unresponsive when rechallenged on normal skin, no matter what the initial sensitizing dose of hapten was. To determine whether other biologic effects of UV also exhibited genetic variation, C3H/HeN and C3H/HeJ mice were compared for susceptibility to UVB-induced skin cancer formation. C3H/HeJ mice developed significantly more tumors than C3H/HeN mice when subjected to a single dose of UV radiation followed by repeated exposure to the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. These studies provide strong evidence that genetic factors influence individual susceptibility to the biologic effects of UV radiation.

C5aR ligand peptide 3D QSAR study performed with an applied linear conformation.

A 3D quantitative structure-activity relationship study (QSAR) of binding and activation of the human C5a receptor by peptide analogs of the C-terminal binding domain of C5a anaphylatoxin is reported. Using published C5a analog affinity and activity data, this paper seeks to elucidate the pharmacophore for the high affinity C-terminal binding domain of the C5a peptide with the molecular modeling technique of comparative molecular field analysis (CoMFA). In order to model peptides for which there was incomplete conformational data, an arbitrary linear conformation was imposed upon the highly flexible C5a analogs. The resulting models yield a crossvalidated q2 of 0.889 and 0.787, for receptor-ligand affinity and EC50 calcium release activity, respectively, suggesting these models have good predictive ability for other test peptides.

Genotypic differences in host immunoreactivity and their effect on the development of polycyclic hydrocarbon-induced tumors.

Polyaromatic hydrocarbons are ubiquitous environmental contaminants that are known primarily for their mutagenic and carcinogenic properties. In mice, when applied to the skin, they also act as antigenic substances, capable of initiating a cell-mediated immune response (contact hypersensitivity). Using dimethylbenz(a)anthracene (DMBA) as a prototype, studies from this laboratory have found that genetic polymorphisms, at the Ah receptor locus, the major histocompatibility complex and the Lps locus, control the magnitude of the cell-mediated immune response to these carcinogenic compounds. Strains of mice that metabolize polyaromatic hydrocarbons well and can be immunized to them are less likely to develop cutaneous tumors when subjected to a polyaromatic hydrocarbon-initiation, TPA-promotion cutaneous carcinogenesis protocol. It may thus be possible to assess individual susceptibility to polyaromatic hydrocarbon-induced tumors by characterizing one's ability to metabolize polyaromatic hydrocarbons and his or her immune response to these agents.

Pharmacokinetics of diltiazem absorption in the rat gastrointestinal tract.

The absorption of diltiazem (CAS 42399-41-7) from the stomach, small intestine, and colon of the rat has been studied, using an in situ cannulation procedure. Diltiazem solutions (1 mg/ml) were prepared in isotonic buffers at pH 3.5 (stomach), 6.2 (small intestine), or 7.5 (colon). 10 ml of drug solution was used in the small intestine, 4 ml was used in the stomach and colon. Aliquot (100 microliters) of the solution was withdrawn at 5-min intervals for a period of 30 min, and assayed by HPLC. A semilog plot of percent remaining vs. time showed that absorption followed apparent first order kinetics with absorption rate constant, ka, equal 0.07 min-1, 0.02 min-1, and 0.01 min-1, in the small intestine, colon, and stomach, respectively.