Ribonucleases (RNases) are a non-mutagenic alternative to harmful DNA-damaging anticancer drugs. Targeting of RNases with antibodies to surface antigens that are selectively expressed on tumor cells endows specificity to the cytotoxic actions of RNases. Barnase, a ribonuclease from Bacillus amyloliquefaciens, is a promising candidate for targeted delivery to cancer cells because of its insusceptibility to the ubiquitous cytoplasmic ribonuclease inhibitor, and its high stability and catalytic activity. Here, we characterized in vitro and in vivo an immunoRNase, scFv 4D5-dibarnase, which consists of two barnase molecules that are fused serially to the single-chain variable fragment (scFv) of humanized 4D5 antibody. The latter is directed against the extracellular domain of human epidermal growth factor receptor 2 (HER2), a cancer marker that is overexpressed in many human carcinomas. The scFv 4D5-dibarnase exerted a specific cytotoxic effect on HER2-overexpressing SKBR-3 and BT-474 human breast carcinoma cells (IC(50) = 4.1 and 2.4 nM, respectively) via induction of apoptosis. Ten doses of 0.7 mg/kg scFv 4D5-dibarnase to BALB/c nude mice that bore SKBR-3 human breast cancer xenografts resulted in a 76% reduction in tumor growth. A single injection of scFv 4D5-dibarnase at a total course dose of 7 mg/kg did not cause severe side effects in BALB/c nude or BDF1 mice. The cytotoxicity and selectivity of scFv 4D5-dibarnase merit consideration of this immunoRNase as a potent anticancer agent.
За последние 10-15 лет оксидазы L-аминокислот (LAAO) стали предметом интенсивного изучения в силу их разнообразного действия на различные биологические объекты. В обзоре суммирована информация об источниках, строении, физико-химических и каталитических свойствах LAAO. Приведены данные о бактериостатических, бактерицидных, противогрибковых, противопротозойных, противовирусных, антипролиферативных и противоопухолевых эффектах этих ферментов, а также о неоднозначном о влиянии на агрегацию тромбоцитов. Особое внимание уделено анализу данных литературы, посвященных выяснению молекулярных механизмов действия LAAO.Основой проявляемых LAAO уникальных свойств является, вероятно, снижение под их действием уровня пула аминокислот (в том числе и незаменимых), а также образование пероксида водорода, влияние которого на клетки опосредовано через АФК и развитие ряда биологических механизмов апоптоза и некроза. Наличие углеводных компонентов в молекулах LAAO способствует их связыванию с поверхностью клеток и созданию высоких локальных концентраций пероксида водорода. Широкий спектр биологических эффектов LAAO in vivo разнообразен и опосредован, как правило, их функциональным значением, например, в головном мозге мышей катализируемая LAAO реакция является единственным путём превращения L-лизина, в молоке мышей LAAO выполняет бактерицидную функцию, а в лейкоцитах LAAO принимают участие в реализации их системного противоинфекционного действия. Протекторный эффект можно также отнести и к оксидазам из других многочисленных источников: микроскопических грибов, ядов змей и морских организмов.Ключевые слова: оксидазы L-аминокислот (LААО), L-лизин-альфа-оксидаза, цитотоксичность, противоопухолевые свойства, противовирусные свойства, апоптоз.ВВЕДЕНИЕ. До 90-х годов прошлого столетия научные исследования оксидаз L-аминокислот (LAAO) были, в основном, посвящены их ферментативным и физико-химическим свойствам [1][2][3][4]. В последние десятилетия интерес к LAAO существенно возрос. Разработаны лабораторные методы выделения и очистки LAAO из многочисленных источников разной природы, изучена первичная структура, а также пространственная структура ряда оксидаз [5][6][7][8]. Получено много интересных данных о биологических эффектах оксидаз L-аминокислот [9][10][11][12][13][14][15][16]. 372* -адресат для переписки
Systemic and intrapleural chemotherapy for metastatic tumor pleurisy was carried out in cats with breast carcinoma. The animals (n=18) were divided into 2 groups. Cats of the systemic chemotherapy group received 3-6 courses of taxotere (30 mg/m(2); n=7) or 3 courses of taxotere (20 mg/m(2)) in combination with doxorubicin (20 mg/m(2)at 21-day intervals (n=5) during the adjuvant period of therapy for metastatic tumor pleurisy. Objective effect was attained in 10 (84.6%) cats: partial remission in 3 (25%) and complete remission in 7 (58.3%, p>0.05) cats. Metastatic pleurisy progressed in 2 (16.7%) cats. The median time to progression reached 1.79 months, median lifespan 2.8 months. The animals of intrapleural chemotherapy group (n=6) received 1-4 courses of cyclophosphamide (250 mg/m(2)) at 1-week interval during the adjuvant period without therapy for malignant pleurisy. Malignant pleurisy progressed in all cats. The median time to progression was equal to median lifespan (0.6 months). The therapy for malignant pleurisy in cats with breast cancer is regarded as the second-line chemotherapy with taxotere preferable as a monotherapy or in combination with doxorubicin.
During the last 10⎯15 years L amino acid oxidases (LAAO) are intensively studied due to their diverse effects on various biological objects. The review summarized information about sources, structure, physicochemical, and catalytic properties of LAAO as well as data on their antibacterial, antifungal, antipro tozoal, antiviral, antiproliferative, and antitumor effects, and on ambiguous effects on platelet aggregation. Special attention is paid to analysis of literature data on elucidation of molecular mechanisms of the LAAO action. It is proposed that the unique properties of LAAO are associated the decrease of L amino acid levels, including the essential amino acids and formation of hydrogen peroxide, which indirectly (via reactive oxy gen species, ROS) acts on cells and triggers biological mechanisms of apoptosis and necroses. The presence of carbohydrate components in LAAO molecules promotes enzyme attachment to the cell surface and cre ation of high local concentrations of hydrogen peroxide. The wide range of biological effects of LAAO in vivo is usually associated with their functional importance. For example, in the mouse brain the LAAO catalyzed reaction is the only reaction for L lysine degradation, while in the mouse milk LAAO acts as a bactericide agent. Leukocyte LAAO is involved in realization of the systemic anti infective effect. The protective action is also attributed to the oxidases from the other numerous sources including microscopic fungi, snake venoms and sea inhabitants.
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