chloroaluminum-tetrasulfophthalocyanine and Urinary-Bladder-Neoplasms

Photodynamic therapy (PDT) consists in administration of a photosensitizer and subsequent irradiation of the tumor with visible light. Routinely the photosensitizer is given intravenously (i.v.). The goal of our study was to examine whether intravesical (i.b.) instillation of the photosensitizer for PDT of bladder cancer might be feasible. Therefore, the uptake of chlor-aluminum-sulfonated phthalocyanine (CASPc) in bladder, bladder tumor, skin, and muscle in a rat bladder cancer model after i.v. injection and i.b. instillation was compared. The efficacy of PDT after either method of administration was also evaluated. The CASPc concentration in bladder tumor after i.v. injection was approximately 1.5-fold that after i.b. instillation. The ratio of CASPc concentration between bladder tumor and normal bladder was approximately 2:1 after administration by either route. There was no systemic absorption of CASPc after i.b. instillation; hence no systemic side effects are expected. PDT showed similar effects on bladder tumor after either method of administration, but less side effects on normal bladder wall after i.b. instillation. Our results demonstrate that i.b. instillation of CASPc for PDT of superficial bladder cancer seems to have advantages over i.v. injection.

Topics: Administration, Intravesical; Animals; Biological Availability; Carcinoma; Indoles; Injections, Intravenous; Microscopy, Fluorescence; Organometallic Compounds; Photochemotherapy; Radiation-Sensitizing Agents; Rats; Tumor Cells, Cultured; Urinary Bladder Neoplasms

The potency of aluminum-chloro-tetrasulfonated phthalocyanine (AlS4Pc) as a photosensitizer in photodynamic therapy was evaluated in in vitro and in vivo studies. Compared with hematoporphyrin derivative (HpD), the following advantages of AlS4Pc were revealed: (1) AlS4Pc was less toxic than HpD in vitro without light irradiation. (2) AlS4Pc showed more photodynamic-dependent cytotoxicity and anti-tumor effect in the red area of the spectrum (> 660 nm) at which tissue penetration is high. (3) AlS4Pc appeared to be removed more rapidly from normal tissues such as muscle and skin. (4) AlS4Pc showed less photodynamic-dependent cytotoxicity in vitro and milder cutaneous phototoxicity in vivo with UVA irradiation. On the basis of these observations, AlS4Pc shows considerable promise as a photosensitizer for PDT.

Topics: Animals; Evaluation Studies as Topic; Hematoporphyrin Photoradiation; Humans; Indoles; Mice; Mice, Inbred C3H; Mice, Nude; Neoplasms, Experimental; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Tumor Cells, Cultured; Urinary Bladder Neoplasms

The role of vascular permeability in the preferential accumulation of photosensitizers in tumor tissue was investigated. Two murine tumors [experimental mammary tumor carcinoma (EMT-6) and methylcholanthrene-induced rhabdomyosarcoma (M1S)] and a human bladder carcinoma (EJ) were grown s.c. on the flank in athymic nude mice and analyzed for in vivo vessel permeability, vascular permeability factor (VPF) secretion, and accumulation of the photosensitizer, chloroaluminum sulfonated phthalocyanine. In vivo tumor vessel permeability and vascular volume were quantitated by measuring Evans blue extravasation and accumulation of a high molecular weight fluoresceinated dextran, respectively. VPF was isolated from serum-free tumor cell conditioned medium using heparin-Sepharose affinity chromatography. Dot and Western blots stained with anti-VPF antiserum positively identified VPF in samples from each tumor. Chloroaluminum sulfonated phthalocyanine pharmacokinetics in tumor-bearing mice were measured using a fiber-based spectrofluorometer. In vivo vessel permeability was found to be greatest in M1S tumors, next in EMT-6 tumors and finally in EJ tumors. Consistent with in vivo data, M1S and EMT-6 tumor cells in culture secrete significantly more VPF than EJ tumor cells. Chloroaluminum sulfonated phthalocyanine accumulation was approximately 2 times greater in M1S and EMT-6 tumors compared to EJ tumors. Our data present evidence that photosensitizer accumulation can be correlated to in vivo tumor vessel permeability and VPF secretion of that tumor. Taken together, the data support the hypothesis that vascular permeability differences among tumors play a significant role in the uptake and retention of photodynamic agents.

Topics: Animals; Capillary Permeability; Culture Media, Conditioned; Culture Media, Serum-Free; Endothelial Growth Factors; Evans Blue; Guinea Pigs; Heparin; Indoles; Lymphokines; Male; Mammary Neoplasms, Experimental; Methylcholanthrene; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Organometallic Compounds; Photosensitizing Agents; Rhabdomyosarcoma; Tissue Distribution; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Photodynamic therapy is an experimental treatment of superficial bladder tumors. Photofrin, a mixture of porphyrins, is the only photosensitizer in clinical use in the U.S.A. and its major side effect is prolonged cutaneous phototoxicity. In order to circumvent this problem of phototoxicity, new photosensitizers are being examined. Cutaneous phototoxicity may also be minimized by local administration of photosensitizer. Therefore, in this study, we investigated the photosensitizer chloro-aluminum sulfonated phthalocyanine (CASPc) in vivo in a rat bladder carcinoma model, and compared two different routes of CASPc administration. AY-27 rat bladder carcinoma cells were transplanted into rat bladders. Eight days after tumor transplantation the biodistribution of CASPc in bladder, skin, muscle and bladder tumor was determined by fluorescence measurements after dye extraction. Photosensitizer administered by intravenous injection and intravesical instillation, were compared. The concentration of CASPc in bladder and bladder tumor after intravenous injection and intravesical instillation was similar. The ratio of dye uptake between tumor and normal bladder after either administration was approximately two. Although no systemic absorption of the photosensitizer was observed after intravesical instillation, there was no reduction in tumor uptake or in the ratio between tumor to normal surrounding tissue. Therefore, no systemic side effects of skin phototoxicity are expected upon intravesical instillation. The microscopic biodistribution of CASPc after intravenous injection and intravesical instillation was also compared. After intravenous injection, the photosensitizer was distributed within the whole tumor with increased fluorescence around the microvasculature. In the normal bladder wall, weak fluorescence was seen in the area of the vasculature in the submucosa and the muscularis. After intravesical instillation, strong fluorescence was detected only at the tumor surface and in normal urothelium; no fluorescence was found in other areas of the tumor or in submucosa or muscularis. A comparison of the photodynamic treatment of model bladder tumors showed that tumor destruction after either method was similar but that there were less side effects to normal bladder wall after intravesical instillation of the CASPc. Intravesical administration of photosensitizers may, therefore, be a viable alternative to intravenous injection with potential for reduced systemic an

Topics: Administration, Intravesical; Animals; Female; Indoles; Injections, Intravenous; Models, Biological; Organometallic Compounds; Photochemotherapy; Radiation-Sensitizing Agents; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

Aluminum-chloro-tetrasulfonated phthalocyanine (PC) showing an absorption peak at 678 nm was compared to hematoporphyrin derivative (HpD), a photosensitizer commonly used in the photodynamic therapy (PDT) of cancers.. KK-47 cells were exposed to long-wavelength ultraviolet (UVA) or red light (greater than 600 nm, greater than 640 nm and greater than 660 nm) after drug sensitization. With UVA irradiation, a higher photodynamic cell killing effect was observed in the cells treated with HpD than with PC. However, with red light irradiation (both greater than 640 nm and greater than 660 nm) PC resulted in greater cell damage. PC was less toxic to KK-47 cells in the dark. In vivo studies: Using a gold vapor laser (GVL: 627.8 nm, 200 mW/cm2, 200 J/cm2), the photodynamic tumor response was determined in C3H/He mice bearing transplantable squamous cell carcinoma. No significant difference was observed in the tumor volume between the PC and HpD groups, except that the PC group (10.0 mg/kg body weight) showed a significantly higher remission rate (3/6) than the control group (0/10, P less than 0.05). Skin photosensitivity test: Skin photosensitivity was estimated by measuring changes in back skin thickness due to photosensitization. With UVA irradiation, a stronger skin reaction was observed in the HpD group, while with visible light irradiation there was no significant difference between the HpD and PC groups. Based on the superior cell killing effect with red light, reduced toxicity to the cells in the dark and mild skin reaction with UVA, PC may be a more promising photosensitizer for PDT.

Topics: Animals; Carcinoma, Squamous Cell; Cell Survival; Hematoporphyrin Photoradiation; Humans; Indoles; Isoindoles; Lasers; Mice; Mice, Inbred C3H; Organometallic Compounds; Photochemotherapy; Skin; Tumor Cells, Cultured; Urinary Bladder Neoplasms

Chloroaluminum tetrasulfophthalocyanine (AlPCS) was used as a photosensitizer for the photodynamic treatment of transplantable N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) induced urothelial tumors. Two groups of six rats each were injected with AlPCS (three micrograms./gm. body weight) and 24 hours after injection underwent photodynamic treatment with red light (greater than 590 nm., 360 joules/cm.2). Tumors examined four hours (Group I) and 24 hours (Group II) after the completion of phototreatment showed extensive hemorrhagic necrosis. Tumors treated with AlPCS alone showed no changes. In two other groups of six rats each, blood flow to tumors treated with AlPCS alone (Group III) and AlPCS plus light (Group IV) was measured using the radioactive microsphere technique. AlPCS plus light resulted in a significant decrease (p less than .05) in tumor blood flow within 10 minutes of completion of phototreatment while AlPCS alone had no effect on tumor blood flow. These findings are similar to those observed when higher doses (10 micrograms./gm. to 20 micrograms./gm. body weight) of hematophorphyrin derivative (HpD) and light were used for phototreatment of FANFT induced tumors. AlPCS is a stable sulfonated derivative of tetraazotetrabenzoporphyrin which absorbs maximally in the red portion of the visible spectrum, a region with good tissue penetration properties. These studies suggest the AlPCS may be a useful new agent for photodynamic therapy of cancer.

Topics: Animals; Indoles; Male; Neoplasm Transplantation; Organometallic Compounds; Rats; Rats, Inbred F344; Regional Blood Flow; Urinary Bladder Neoplasms