ABSTRACT
We present an extremely rare clinical case of a 38-year-old Russian patient with multiple malignant neoplasms of the uterus and colon caused by genetically confirmed two hereditary diseases: Diamond-Blackfan anemia and Lynch syndrome. Molecular genetic research carried out by various methods (NGS, Sanger sequencing, aCGH, and MLPA) revealed a pathogenic nonsense variant in the MSH6 gene: NM_000179.2: c.742C>T, p.(Arg248Ter), as well as a new deletion of the chromosome 15's locus with the capture of 82,662,932-84,816,747 bp interval, including the complete sequence of the RPS17 gene. The lack of expediency of studying microsatellite instability in endometrial tumors using standard mononucleotide markers NR21, NR24, NR27, BAT25, BAT26 was demonstrated. The estimated prevalence of patients with combination of Diamond-Blackfan anemia and Lynch syndrome in the world is one per 480 million people.
ABSTRACT
BACKGROUND: Conventional antitumor Photosensitizers (PS) are normally low toxic in the dark whereas light activation triggers massive cell death (photodynamic therapy, PDT). OBJECTIVE: To expand the therapeutic potential of PS to dual potency cytocidal agents, taking advantage of the use of bacteriopurpurin for a deeper tissue penetration of light, and suitability of the tetrapyrrolic macrocycle for chemical modifications at its periphery. METHODS: Conjugation of a pro-oxidant thiolate Au (I) moiety to the bacteriopurpurin core and evaluation of cytotoxicity in cell culture and in vivo. RESULTS: New water-soluble derivatives showed micromolar cytotoxicity for cultured human tumor cell lines in the dark, including the subline with an altered drug response due to p53 inactivation. Cellular PDT with the selected conjugate, thiolate Au (I)-dipropoxybacteriopurpurinimide (compound 6) with two triphenylphosphine Au fragments, triggered rapid (within minutes) cell death. Damage to the plasma membrane (necrosis) was a hallmark of cell death by compound 6 both in the dark and upon light activation. Furthermore, one single i.v. injection of compound 6 caused retardation of transplanted syngeneic tumors at the tolerable dose. Illumination of tumors that accumulated compound 6 significantly synergized with the effect of 6 in the dark. CONCLUSION: Complexes of virtually non-toxic, photoactivatable bacteriopurpurin with the gold-containing organic moiety are considered the dual potency antitumor agents, tentatively applicable for intractable tumors.
Subject(s)
Antineoplastic Agents/pharmacology , Gold/pharmacology , Light , Organogold Compounds/pharmacology , Pheophytins/pharmacology , Sulfhydryl Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Gold/chemistry , HCT116 Cells , Humans , Molecular Structure , Organogold Compounds/chemical synthesis , Organogold Compounds/chemistry , Pheophytins/chemistry , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , Tumor Cells, CulturedABSTRACT
"Radachlorin"(®), also known in the EU as Bremachlorin, a composition of 3 chlorophyll a derivatives in an aqueous solution, was introduced into the Russian Pharmacopoeia. Its GMP (Good Manufacturing Practice) facility based manufacturing method was patented. Laboratory experiments and clinical phase I were performed. Protocols were designed for PDT of basal cell carcinoma of the skin to result in GCP (Good Clinical Practice)-conformed randomized phase II clinical studies. "Radachlorin"(®) solution for intravenous infusions 0.35% 10mL in the doses of 0.5-0.6 and 1.0-1.2mg/kg and a gel for topical application 0.1% 25g in the dose of 0.1g/cm(2) were photoactivated by 2.5W 662nm semiconductor laser "LAKHTA-MILON(®)" (St. Petersburg, Russia) in light doses of 200, 300 (solution), 400, 600, 800 (gel) J/cm(2). Safety study showed no side effects and a good tolerability of "Radachlorin"(®) by patients. There was no normal skin/subdermal tissue damage after both laser and sun light exposure. The main part (98%) of the drug was excreted or metabolized in the first 48h. Drug administration at a dose of 1.0-1.2mg/kg and irradiation at 3h with 662±3nm light at a dose of 300J/cm(2) (solution) and 4 PDT sessions at an interval of 1 week with 3h gel exposure, followed by 400J/cm(2) light exposure (gel) were found to be the optimal treatment regimes. Having successfully passed clinical trials, "Radachlorin"(®) achieved marketing authorization in Russia in 2009 and a conditional approval in South Korea in 2008. It is a candidate for phase III clinical trials in the EC and may be commercialized as a prospective second-generation photosensitizer.
Subject(s)
Carcinoma, Basal Cell/drug therapy , Chlorophyll/analogs & derivatives , Photochemotherapy , Photosensitizing Agents/therapeutic use , Porphyrins/therapeutic use , Skin Neoplasms/drug therapy , Chlorophyll/adverse effects , Chlorophyll/pharmacokinetics , Chlorophyll/therapeutic use , Dose-Response Relationship, Drug , Drug Combinations , Female , Humans , Male , Photosensitizing Agents/adverse effects , Photosensitizing Agents/pharmacokinetics , Porphyrins/adverse effects , Porphyrins/pharmacokineticsABSTRACT
In 1992-2006 at P.A. Hertsen Moscow Oncology Research Institute photodynamic therapy (PDT) was performed in 48 esophageal cancer patients (total 48 lesions). For PDT we used Russian photosensitizers (Photogem, Photosens, Radachlorin, Alasens), Russian diode lasers (Crystall) and endoscopic equipment. As a result of PDT complete regression was in 77% of esophageal cancer lesions, partial regression was in 23%. The follow-up period was 3-11 years. Median of survival was in 4.59 years of esophageal cancer patient.
