chlorophyll-a and Adenocarcinoma

Photodynamic therapy (PDT) with porfimer sodium, FDA approved to treat premalignant lesions in Barrett's esophagus, causes photosensitivity for 6-8 weeks. HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) shows minimal photosensitization of short duration and promising efficacy in preclinical studies. Here we explore toxicity and optimal drug and light dose with endoscopic HPPH-PDT. We also want to know the efficacy of one time treatment with HPPH-PDT.. Two nonrandomized dose escalation studies were performed (18 patients each) with biopsy-proven high grade dysplasia or early intramucosal adenocarcinoma of esophagus. HPPH doses ranged from 3 to 6 mg/m2 . At 24 or 48 hours after HPPH administration the lesions received one endoscopic exposure to 150, 175, or 200 J/cm of 665 nm light.. Most patients experienced mild to moderate chest pain requiring symptomatic treatment only. Six patients experienced grade 3 and 4 adverse events (16.6%). Three esophageal strictures were treated with dilatation. No clear pattern of dose dependence of toxicities emerged. In the drug dose ranging study (light dose of 150 J/cm at 48 hours), 3 and 4 mg/m2 of HPPH emerged as most effective. In the light dose ranging study (3 or 4 mg/m2 HPPH, light at 24 hours), complete response rates (disappearance of high grade dysplasia and early carcinoma) of 72% were achieved at 1 year, with all patients treated with 3 mg/m2 HPPH plus 175 J/cm and 4 mg/m2 HPPH plus 150 J/cm showing complete responses at 1 year.. HPPH-PDT for precancerous lesions in Barrett's esophagus appears to be safe and showing promising efficacy. Further clinical studies are required to establish the use of HPPH-PDT.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Barrett Esophagus; Chlorophyll; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Administration Schedule; Esophageal Neoplasms; Esophagoscopy; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Photochemotherapy; Photosensitizing Agents; Precancerous Conditions; Treatment Outcome

Lung adenocarcinoma is a leading human malignancy with fatal prognosis. Ninety percent of the deaths, however, are caused by metastases. The model of subcutaneous tumor xenograft in nude mice was adopted to study the growth of control and photodynamically treated tumors derived from the human A549 lung adenocarcinoma cell line. As a side-result of the primary studies, observations on the metastasis of these tumors to the murine lungs were collected, and reported in the present paper. The metastasizing primary tumors were drained by a prominent number of lymphatic vessels. The metastatic tissue revealed the morphology of well-differentiated or trans-differentiated adenocarcinoma. Further histological and histochemical analyses demonstrated the presence of golden-brown granules in the metastatic tissue, similar to these found in the tumor tissue. In contrast to the primary tumors, the electron paramagnetic resonance spectroscopy revealed no nitric oxide - hemoglobin complexes (a source of intense paramagnetic signals), in the metastases. No metastases were found in other murine organs; however, white infarctions were identified in a single liver. Taken together, the A549-derived tumors growing subcutaneously in nude mice can metastasize and grow on site in the pulmonary tissue. Thus, they can represent an alternative for the model of induced metastatic nodule formation, following intravenous administration of the cancerous cells.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Cell Line, Tumor; Chlorophyll; Electron Spin Resonance Spectroscopy; Humans; Injections, Subcutaneous; Light; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Photosensitizing Agents; Skin Neoplasms; Transplantation, Heterologous

Our previous study has shown a prolonged retention and accumulation of Zn-pheophorbide a, a water-soluble derivative of chlorophyll a, in tumor tissue (Szczygiel et al. [19]). This prompted us to further evaluate the phototherapeutic potential of this photosensitizer of excellent physicochemical properties.. Cellular uptake of Zn-pheophorbide, its localization in cells, cytotoxicity, phototoxicity and cell death mechanisms were studied in human adenocarcinoma cell lines: A549, MCF-7 and LoVo. The PDT efficacy was tested against A549 tumors growing in nude mice.. Zn-pheophorbide a even at very low concentrations (∼1×10(-6)M) and at low light doses (5J/cm(2)) causes a strong photodynamic effect, leading to 100% cell mortality. Confocal microscopy showed that in contrast to most derivatives of chlorophyll, Zn-pheophorbide a does not localize to mitochondria. The photodynamic effects and the cell death mechanisms of Zn-pheophorbide a, its Mg analog (chlorophyllide a) and Photofrin were compared on the A549 cells. Zn-pheophorbide a showed the strongest photodynamic effect, at low dose killing all A549 cells via apoptosis and necrosis. The very high anti-cancer potential of Zn-pheophorbide was confirmed in a photodynamic treatment of the A549 tumors. They either regressed or were markedly inhibited for up to 4 months after the treatment, resulting, on average, in a 5-fold decrease in tumor volume.. These results show that Zn-pheophorbide a is a very promising low-cost, synthetically easily accessible, second generation photosensitizer against human cancer.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Chlorophyll; Disease Models, Animal; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Photochemotherapy; Photosensitizing Agents; Treatment Outcome; Zinc

In this study, we reported on the synthesis and biological evaluation of radiolabeled fluorescent dye conjugated bovine serum albumin nanoparticles within the size range 190-210 nm. The bovine serum albumin nanoparticles (BSANPs) were prepared using a desolvation method, and chemical cross-linking was performed using gluteraldehyde. Furthermore, pheophorbide-a (PH-A) was loaded on the BSANPs. The results obtained from dynamic light scattering and electron microscopy have proved that nanoparticles are highly monodisperse and near-spherical shaped. The photo-physical properties of the PH-A-BSANPs were obtained using the spectrophotometric techniques. According to the results, PH-A and BSANPs show high non-covalent interaction. PH-A loaded nanoparticles were labeled with (99m)Tc and the radio-labeling efficiency was determined as 90 ± 1.2%. Biodistribution studies of (99m)Tc labeled PH-A-BSANPs and PH-A were carried out using female Albino Wistar rats, and (99m)Tc-PH-A-BSANPs showed a significantly higher uptake in the breast and uterus than (99m)Tc-PH-A. Cell culture study was carried out in MCF-7 cell line (human breast adenocarcinoma cell line). According to the cell culture studies, (99m)Tc-PH-A-BSANPs showed a higher uptake than (99m)Tc-PH-A. Moreover, PH-A-BSANPs demonstrated good photo-physical properties and BSANPs increased the uptake of PH-A on to the MCF-7 cell line. These results confirm that (99m)Tc labeled PH-A-BSANPs could be utilized for radioimaging.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Chlorophyll; Cross-Linking Reagents; Drug Carriers; Female; Glutaral; Humans; Light; Magnetic Resonance Spectroscopy; Mass Spectrometry; Microscopy, Electron; Microscopy, Fluorescence; Molecular Imaging; Nanoparticles; Particle Size; Radiation-Sensitizing Agents; Radiopharmaceuticals; Rats; Rats, Wistar; Scattering, Radiation; Serum Albumin, Bovine; Spectrophotometry, Ultraviolet; Technetium; Tissue Distribution

Scutellaria barbata is a traditional Chinese medicine for cancer treatments. Pheophorbide-a (Pa), one of the active components isolated from this herbal medicine has been proposed to be a potential natural photosensitizer for photodynamic therapy. The anti-tumor effect of pheophorbide-a based photodynamic therapy (Pa-PDT) has been successfully demonstrated in a wide range of human malignant cell lines. However, the effectiveness of Pa-PDT has not yet been evaluated on human breast cancer, which is documented as the second common and the fifth most lethal cancer worldwide.. The cytotoxicity of Pa-PDT was evaluated by using an estrogen receptor (ER)-negative human breast adenocarcinoma cell line MDA-MB-231. The involvement of mitochondria was revealed by the change of mitochondrial membrane potential and the increase of intracellular reactive oxygen species (ROS). The hallmarks of apoptosis, ER stress and autophagy were also assessed by DNA fragmentation, Western blotting, and immunostaining assays.. Pa-PDT showed inhibitory effect on the growth of MDA-MB-231 cells with an IC(50) value of 0.5 microM at 24h. Mitogen-activated protein kinase (MAPK) pathway was found to be triggered, where activation of c-Jun N-terminal kinase (JNK) and inhibition of extracellular signal-regulated kinase (ERK) were occurred in the Pa-PDT-treated cells. Our findings suggested that Pa-PDT exhibited its anti-tumor effects by the activation of mitochondria-mediated apoptosis and the ERK-mediated autophagy in MDA-MB-231 cells.. The present study suggested Pa-PDT is a potential protocol for the late phase human breast cancer, and it is the first study to demonstrate the Pa-PDT induced autophagy contributed to the anti-tumor effects of Pa-PDT on human cancer cells.

Topics: Adenocarcinoma; Apoptosis; Autophagy; Breast Neoplasms; Cell Line, Tumor; Chlorophyll; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Plant Extracts; Protein Kinase Inhibitors; Radiation-Sensitizing Agents; Receptors, Estrogen; Scutellaria

Three pheophorbide-related compounds (1-3) were isolated from the leaves and stems of Clerodendrum calamitosum. The methyl ester of 3 (6) and the known (10S)-hydroxypheophytin a (7) also were isolated from leaves of the related plant Clerodendrum cyrtophyllum. Compounds 1 and 6 were isolated for the first time as naturally occurring products from a plant source. All structures were elucidated by detailed spectroscopic analysis. Biological evaluation showed that 1 and 2 exhibited strong cytotoxicity against human lung carcinoma (A549), ileocecal carcinoma (HCT-8), kidney carcinoma (CAKI-1), breast adenocarcinoma (MCF-7), malignant melanoma (SK-MEL-2), ovarian carcinoma (1A9), and epidermoid carcinoma of the nasopharynx (KB), and its etoposide- (KB-7d), vincristine- (KB-VCR), and camptothecin-resistant (KB-CPT) subclones. Compound 3 was less cytotoxic than 1 and 2. Compounds 4-6, the methyl esters of 1-3, showed strongly increased cytotoxicity compared with the parent acids. Interestingly, 6 was the most active derivative among these compounds. Compound 7 was inactive.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Camptothecin; Cell Survival; Chlorophyll; Dose-Response Relationship, Drug; Drug Resistance; Etoposide; Female; Humans; Ileal Neoplasms; KB Cells; Kidney Neoplasms; Lung Neoplasms; Magnetic Resonance Spectroscopy; Melanoma; Molecular Structure; Ovarian Neoplasms; Plant Leaves; Plant Stems; Plants, Medicinal; Stereoisomerism; Structure-Activity Relationship; Taiwan; Tumor Cells, Cultured; Vincristine

We present in vivo fluorescent, near-infrared (NIR), reflectance images of indocyanine green (ICG) and carotene-conjugated 2-devinyl-2-(1-hexyloxyethyl) pyropheophorbide (HPPH-car) to discriminate spontaneous canine adenocarcinoma from normal mammary tissue. Following intravenous administration of 1.0 mg kg-1 ICG or 0.3 mg kg-1 HPPH-car into the canine, a 25 mW, 778 nm or 70 mW, 660 nm laser diode beam, expanded by a diverging lens to approximately 4 cm in diameter, illuminated the surface of the mammary tissue. Successfully propagating to the tissue surface, ICG or HPPH-car fluorescence generated from within the tissue was collected by an image-intensified, charge-coupled device camera fitted with an 830 or 710 nm bandpass interference filter. Upon collecting time-dependent fluorescence images at the tissue surface overlying both normal and diseased tissue volumes, and fitting these images to a pharmacokinetic model describing the uptake (wash-in) and release (wash-out) of fluorescent dye, the pharmacokinetics of fluorescent dye was spatially determined. Mapping the fluorescence intensity owing to ICG indicates that the dye acts as a blood pool or blood persistent agent, for the model parameters show no difference in the ICG uptake rates between normal and diseased tissue regions. The wash-out of ICG was delayed for up to 72 h after intravenous injection in tissue volumes associated with disease, because ICG fluorescence was still detected in the diseased tissue 72 h after injection. In contrast, HPPH-car pharmacokinetics illustrated active uptake into diseased tissues, perhaps owing to the overexpression of LDL receptors associated with the malignant cells. HPPH-car fluorescence was not discernable after 24 h. This work illustrates the ability to monitor the pharmacokinetic delivery of NIR fluorescent dyes within tissue volumes as great as 0.5-1 cm from the tissue surface in order to differentiate normal from diseased tissue volumes on the basis of parameters obtained from the pharmacokinetic models.

Topics: Adenocarcinoma; Animals; Carotenoids; Chlorophyll; Dog Diseases; Dogs; Female; Indocyanine Green; Mammary Neoplasms, Animal; Photosensitizing Agents; Spectrometry, Fluorescence; Spectroscopy, Near-Infrared

Selective histological necrosis of experimental pancreatic carcinoma by photodynamic therapy (PDT) has been successful with haematoporphyrin derivatives and phthalocyanine as photosensitizers. This report describes the feasibility of PDT with pheophorbide A as the photosensitizer to treat azaserine-induced pancreatic rat carcinoma and analyses survival of the animals. An organ distribution study 24 h after pheophorbide A administration (9 mg/kg intravenously) gave a selectivity ratio of 13.5:1 between tumour and surrounding tissue. Light of 660 nm and 100 J/cm2 induced selective necrosis of the tumour. Six of nine rats were cured in 120 days whereas all 36 control animals died within 35 days (P < 0.01). The pancrease and hepatic pedicle were relatively unaffected by PDT, but the duodenum was injured.

Topics: Adenocarcinoma; Animals; Chlorophyll; Duodenum; Necrosis; Pancreas; Pancreatic Neoplasms; Photochemotherapy; Radiation-Sensitizing Agents; Rats; Rats, Inbred Lew; Survival Analysis; Time Factors