talaporfin and Liver-Neoplasms

Despite therapeutic advances, cancer remains the cause of an estimated 23% of deaths in the USA. New treatments for malignancy are greatly needed.. Talaporfin sodium is a light-activated drug that causes tissue death through induction of apoptosis. Systemic antitumor effects mediated by CD8(+) T cells have been demonstrated in preclinical studies, providing a mechanism for distant response of tumors noted in clinical trials. Talaporfin sodium is approved in Japan for early-stage endobronchial cancer. Phase I and II studies in solid tumors have shown tumor regression in patients refractory to other therapies. Phase III pivotal studies against hepatocellular carcinoma as monotherapy and liver-metastatic colorectal cancer in combination with chemotherapy are ongoing. Talaporfin sodium is also in studies in men with symptomatic benign prostatic hyperplasia. Substantial safety data from clinical trials so far indicate that the drug is well tolerated.. Talaporfin sodium has a broad safety profile and a mode of action that could affect growth in treated and untreated tumors.. Clinical and preclinical studies indicate that talaporfin sodium treatment may offer a powerful option to synergize current therapies, as well as an alternative monotherapy in treating cancer.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Carcinoma, Hepatocellular; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Combined Modality Therapy; Humans; Japan; Liver Neoplasms; Male; Neoplasm Staging; Neoplasms; Oxides; Porphyrins

Twenty-seven patients with refractory liver metastases from colorectal cancer took part in a Phase II study of the light infusion technology (Litx) light-activated drug/device system to assess safety and evaluate time to tumor progression (TTP).. Litx consists of the light-activated drug, talaporfin sodium (LS11), activated intratumorally by a catheter-like array of light-emitting diodes (LEDs). After placement of the array via ultrasound or computed tomography (CT) guidance, LS11 was administered intravenously, followed 15-60 min later by light infusion for 2.8 hr. Patients were assessed for adverse events and tumor response using physical examination, laboratory values, and CT scan evaluation over a period of 60 days.. The observed occurrence of Litx treatment-related adverse events was minimal and cumulative toxicity did not occur when combined with chemotherapy. Assessment of TTP and tumor response rate, although statistically non-robust, suggest potential improvement.. The Litx system was shown to be safe for treating liver metastases from colorectal cancer and there was no cumulative toxicity when combined with standard systemic therapy. Preliminary assessments of TTP and tumor response rate justify further evaluation in a Phase III follow-up study.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Colorectal Neoplasms; Combined Modality Therapy; Disease Progression; Female; Humans; Liver Neoplasms; Male; Middle Aged; Photosensitizing Agents; Phototherapy; Porphyrins; Time Factors

Reactive oxygen species (ROS) can induce lysosomal membrane permeabilization (LMP). Photoirradiation of murine hepatoma 1c1c7 cultures preloaded with the photosensitizer NPe6 generates singlet oxygen within acidic organelles and causes LMP and the activation of procaspases. Treatment with the cationic amphiphilic drugs (CADs) U18666A, imipramine, and clozapine stimulated the accumulation of filipin-stainable nonesterified cholesterol/sterols in late endosomes/lysosomes, but not in mitochondria. Concentration-response studies demonstrated an inverse relationship between lysosomal nonesterified cholesterol/sterol contents and susceptibility to NPe6 photoirradiation-induced intracellular membrane oxidation, LMP, and activation of procaspase-9 and -3. Similarly, the kinetics of restoration of NPe6 photoirradiation-induced LMP paralleled the losses of lysosomal cholesterol that occurred upon replating U18666A-treated cultures in CAD-free medium. Consistent with the oxidation of lysosomal cholesterol, filipin staining in U18666A-treated cultures progressively decreased with increasing photoirradiating light dose. U18666A also suppressed the induction of LMP and procaspase activation by exogenously added hydrogen peroxide. However, neither U18666A nor imipramine suppressed the induction of apoptosis by agents that did not directly induce LMP. These studies indicate that lysosomal nonesterified cholesterol/sterol content modulates susceptibility to ROS-induced LMP and possibly does so by being an alternative target for oxidants and lowering the probability of damage to other lysosomal membrane lipids and/or proteins.

Topics: Androstenes; Animals; Anticholesteremic Agents; Apoptosis; Carcinoma, Hepatocellular; Caspase 9; Cell Membrane Permeability; Cholesterol; Endosomes; Filipin; Intracellular Membranes; Light; Liver Neoplasms; Lysosomes; Mice; Mitochondria; Oxidants; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species; Tumor Cells, Cultured

Recent studies have demonstrated an effect of photodamage on the endocytic pathway involved in recycling of membrane components. Using a series of agents with known sub-cellular targets, we explored the determinants of photodynamic inhibition of endocytic processes in three cell lines: A murine leukemia, a murine hepatoma, and a non-malignant epithelial cell line of human origin.. The PI-3 kinase antagonist wortmannin blocks endosomal processing pathway dependent on this enzyme, providing an indication of the "flux" of endocytosis. Microscopic observations were used to assess the effect of photodamage on this pathway. Photosensitizing agents specific for mitochondrial, endoplasmic reticulum (ER), lysosomal, and endosomal photodamage were employed.. Sub-lethal photodamage directed against endosomes or lysosomes interrupted early steps in this endocytic process in the hepatoma cell line. A mechanism for these effects is proposed. Mitochondrial photodamage could interrupt endocytosis, but at levels that also induced apoptosis. ER photodamage did not affect endocytosis even at lethal levels. Somewhat similar results were obtained with other cell lines, but there were sufficient differences to indicate that the cell phenotype is, in part, a determinant of the endocytic response to PDT.. PDT is therefore seen to have an effect on endocytic processes. Further work will be needed to delineate the role of these endocytic effects in the array of responses to photodynamic therapy.

Topics: Androstadienes; Animals; Carcinoma, Hepatocellular; Cell Line; Cell Line, Tumor; Endocytosis; Epithelial Cells; Humans; Indoles; Leukemia; Liver Neoplasms; Mesoporphyrins; Mice; Models, Biological; Organelles; Organometallic Compounds; Phosphodiesterase Inhibitors; Photochemotherapy; Photosensitizing Agents; Porphyrins; Wortmannin

Irradiation of murine hepatoma 1c1c7 cultures presensitized with N-aspartyl chlorin e6 (NPe6) caused lysosomal disruption and apoptosis. Tao cells, a variant of the 1c1c7 line having lower aryl hydrocarbon receptor (AhR) contents, were resistant to the pro-apoptotic effects of NPe6 in the same photodynamic therapy protocol. Colony-forming assays were used to establish light dose-dependent and NPe6 concentration-dependent cytotoxicity curves. Lysosomal breakage and cell survival paralleled one another in both cell types. When analyzed at comparable lethal dose conditions, the onset of apoptosis was delayed, and the magnitude of the apoptotic response was muted in Tao cells, as assessed by morphology, annexin V binding, caspase-3 activities, and analyses of Bid, procaspase-9, and pro-caspase-3 cleavage. In contrast, the kinetics/magnitude of pro-caspase-3 activation in the two cell lines were identical after exposure to HA14 -1 or Jo2 antibody, inducers of the intrinsic and extrinsic apoptotic pathways, respectively. Tao endosomal/lysosomal extracts contained approximately 50%, 35%, and 55% of the Bid cleavage and cathepsin B and D activities of 1c1c7 endosomes/lysosomes, respectively. Western blot analyses confirmed reduced cathepsin B/D contents in Tao cells. Analyses of 1c1c7/Tao variants engineered to express antisense/sense AhR constructs suggested that endosomal/lysosomal cathepsin B and D content, but not whole cell content, correlated with AhR expression. These studies provide a mechanism for the resistance of Tao cultures to the proapoptotic effects of a protocol causing targeted disruption of lysosomes. They also suggest that the AhR, in the absence of exogenous ligand, may affect the trafficking/processing of proteases normally found in endosomes/lysosomes.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzopyrans; BH3 Interacting Domain Death Agonist Protein; Carcinoma, Hepatocellular; Carrier Proteins; Cathepsins; fas Receptor; Liver Neoplasms; Lysosomes; Mice; Nitriles; Photosensitizing Agents; Porphyrins; Receptors, Aryl Hydrocarbon; Triazenes; Tumor Cells, Cultured