Fluorescent diagnosis and photodynamic therapy for C6 glioma in combination with antiangiogenic therapy in subcutaneous and intracranial tumor models.

OBJECTIVE: Investigating the distinctions pharmacokinetics of chlorin e6 conjugated with polyvinyl pyrrolidone photosensitizer (Ce6CPPPS)in healthy and tumor tissues of rat brain and evaluating the antitumor efficacy of combination treatment for C6 rat glioma including photodynamic (PDT) and antiangiogenic therapy (AAT). MATERIALS AND METHODS: The study was performed on 50 white random-bred rats in subcutaneous and intracranial models of C6 glioma. Photosensitizer (PS) Ce6CPPPS single injection at a dose of 2.5 mg/kg was made into the animal's caudal vein. The PS accumulation level in brain tissues and C6 rat glioma was measured with spectral fluorescence technique using LESA-01-Biospek spectrum analyser (Russian Federation, Moscow; λ = 632.8 nm). Photoirradiation of intracranial and subcutaneous C6 glioma was carried out with a light exposure dose of 50 J/cm(2) (IMAF-Axicon, Republic of Belarus; λ = 661 nm). AAT drug bevacizumab, single injection was made intravenously at a dose of 10 mg/kg 24 h after tumor photoirradiation. The criteria for efficacy evaluation were mean survival time (MST) and median survival of the animals in the study group vs the control and the -percentage of tumor necrosis areas induced by the above-mentioned treatment. RESULTS: The optimal time for photoirradiation of intracranial C6 glioma is 0.5 h after Ce6CPPPS injection. The combination therapy group demonstrated a statistically significant MST increase (38.4 ± 4.39 days) compared with the PDT group (29.2 ± 3.5 days) (p = 0.02) and the AAT group (27.1 ± 2.74 days) (p = 0.02). Necrosis areas in tumor tissue were as follows: the intact control - 10.0 ± 2.55%, PDT - 54.87 ± 6.95% (p = 0.003), AAT - 57.83 ± 6.53% (p = 0.003) and combination therapy - 89.43 ± 5.57% (p = 0.001). CONCLUSIONS: This paper is the first report about feasibility of efficient use of PDT with a PS of chlorin series and AAT with bevacizumab for the treatment of brain tumors in experimental models.

Experimental study of antiangiogenic and photodynamic therapies combination for treatment of peritoneal carcinomatosis: preliminary results.

AIM: To create adequate orthotopic model of peritoneal carcinomatosis in rats using a transplantable rat tumor M-1 sarcoma, to assess the early tumor response after intraperitoneal photodynamic and/or antiangiogenic therapy for peritoneal carcinomatosis. METHODS: In 14-18 days after intraperitoneal inoculation, eighteen tumor-bearing animals were divided into three groups and undergone intraperitoneal photodynamic therapy and/or antiangiogenic therapy. Assessment of the tumor posttreatment changes was performed using a method of vital staining with Evans blue, MRI-monitoring and morphologic investigation. RESULTS: Percentage of necrosis in disseminated tumors of animals undergone combination therapy significantly higher then after each of the methods alone and achieved 89.46% vs 41.47% after antiangiogenic therapy and 69.73% after photodynamic therapy. Contrast-enhanced MRI showed entirely necrotic tumor nodes in rats undergone the combination therapy. Morphologic study confirmed that tumor response after combination therapy was characterized by maximal spread of necrotic and inflammatory changes in tumor. CONCLUSION: Preliminary results demonstrate enhance of the treatment outcome after combination of antiangiogenic and intraperitoneal photodynamic therapies for peritoneal carcinomatosis in rats.

Photodynamic therapy of cervical intraepithelial neoplasia grades II and III with Photolon.

The objective of the present study was to test in clinics a previously developed novel organ-saving approach for the treatment of CIN using PDT with the photosensitizer Photolon applied in women of a childbearing age with CIN II and III. A total number of 112 patients aged 35.2+/-1.6 with morphologically proven diagnosis of CIN II and III were enrolled into the study. All 112 patients had been observed at least during 1-year follow-up period after PDT. Among them 53 patients (44.1%) were subjected to a dynamic observation for less than 2 years; 29 patients (24.1%) were under the observation for less than 3 years; 13 patients (10.8%) - for 3-4 years and 17 women - for more than 4 years. A complete response represented by the complete regression of neoplastic lesions, which was proved by the results of morphological examinations, was revealed in 104 (92.8%) of treated women. In 3 months after treatment a complete eradication of the HPV infection was proven by PCR-analysis in 47 (53.4%) from 88 patients who have been infected with HPV of a highly oncogenic strains before PDT. PDT with Photolon is an alternative approach for the treatment of cervical intraepithelial neoplasia which can be recommended for women of childbearing age. The simplicity of the procedure as well as its' high therapeutic efficacy defines the reasonability of its' introduction into the clinical practice as a new organ-saving method for the treatment of patients with cervical intraepithelial neoplasia.

Pharmacokinetics and biodistribution of Photolon (Fotolon) in intact and tumor-bearing rats.

BACKGROUND: This paper provides the results of the non-clinical evaluation of biodistribution of the PS Photolon in inner organs and tissues of intact and tumor-bearing rats with xenograft tumors of different morphologic types. METHODS: The accumulation studies were performed in rats by means of intravital laser fluorimetry in situ and spectrophotometric determination ex vivo. RESULTS: The biodistribution pattern of Photolon does not depend on tumor carriage as well as on morphologic type of the xenograft tumor. We have also showed that Photolon easily crosses an intact blood-brain barrier and accumulates in tissues of central nervous system. The relative bioavailability of brain tissues for Photolon was estimated as 82%, T(max)-30 min, mean residual time (MRT)-1.6h. CONCLUSIONS: In general, results of the experimental study of biodistribution of Photolon in inner organs and tissues of rats, performed as in real time (by means of intravital laser fluorimetry in situ) as ex vivo (spectrophotometric assay) can be utilized while optimizing existing regimens of PDT with the purpose to increase safety and efficacy of treatment as well as for the development of new PDT protocols with Photolon applied for new indications. Parameters of pharmacokinetics and biodistribution of Photolon/Fotolon as well as its' ability to cross an intact blood-brain barrier, are optimal for the majority of modern clinical applications of PDT.

The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro.

AIM: To evaluate the effect of cell oxygenation on photocytotoxicity of a novel tricarbocyanine indolenine dye covalently bound to glucose (TICS). METHODS: HeLa cells were incubated with 5 microM TICS, 2 h later irradiated by laser at 740 nm with a light dose of 10 J/cm(2), delivered at a power density of 10, 20, 25 or 30 mW/cm(2), in air or in argon atmosphere, and then scored for viability. RESULTS: The photocytotoxicity of TICS increased dramatically as the power density was reduced. Under hypoxia TICS-photosensitized cell death was determined but its value was lowered, compared to photoirradiation in the air. CONCLUSION: Photosensitizing effect of TICS is only partially dependent on the oxygenation of tumor cells.

Modifying effect of organocobalt complexes on the tumour response to anticancer treatments.

A new type of agents are proposed for combined cancer therapy. They are organocobalt (III) chelates containing a sigma-bounded organyl group and a mixed tridentate ligand derived from a Schiff base. These complexes generate free radicals due to the action of protons in physiological ranges of pH and temperature, and hence are conceivably capable of selectively attacking a malignant neoplasm that is slightly acidic and can be made even more so by introducing some means intensifying glycolysis. An in vivo examination was performed using transplanted rat tumours (Guerin and Walker 256 carcinomas, Sarcoma 45). The modifying effect of one of these complexes on the tumour response to cis-DDP, radiation and/or local hyperthermia was tested by means of tumour growth delay assay and local tumour control. The potentiating effect of the complex was maximal when it was administered 60-90 minutes prior to other agents (cisDDP, X-irradiation heat). The enhancement ratio was found to be ca. 2.0-4.0 for cisDDP and 2.0 for radiation. In conclusion, in our tumour models, an increase of the antitumour effect was obtained for conventional antitumour agents when they were supplemented with organocobalt complex. It can be hypothesised that DNA in tumour cells may be considered to be the main target for organocobalt complexes.