The main objective of this study was the characterization of preclinical tumor models based on their expression of alpha-fetoprotein receptor (RECAF) for targeting cancer cells with a new non-covalent complex (AIMPILA) containing alpha-fetoprotein as the carrier and Atractyloside as an apoptosis-inducing agent. For that purpose, we measured the amount of RECAF in the homogenates of the grafted tumors T47D and SW620 and in HepG2 cell extracts. We also determined the alpha-fetoprotein binding specificity of the targeting drug AIMPILA using a solid-phase chemiluminescent assay with AIMPILA-Acrdidinium. We found that RECAF is practically absent from healthy mice tissues (100 Units/mg) where in malignant cells, the amount of alpha-fetoprotein receptors follows this order: T47D (9152 Units/mg) > HepG2 (4865 Units/mg) > SW620 (2839 Units/mg). This agrees with our findings regarding AIMPILA-induced tumor growth inhibition (T47D (T/C = 22%) > HepG2 (T/C = 51%) > SW620 (T/C = 70%), where T/C is the ratio of tumor volume in treated vs control animals). Our results demonstrate that the therapeutic response to the targeting drug AIMPILA strongly depends on the RECAF expression by human tumors and confirms the choice of the tumor models used for an AIMPILA preclinical study.
Research is devoted to the study of the ability of the labeled complex «AIMPILA-ACRIDIN» and the test compound «AFP-ACRIDIN» in concentration of 1.0 mkg/ml to internalize in a small intestine. For this purpose there was used the modified technique of the isolated inverted small intestinal sac method in rats with the aid of by ourselves delivered technique with the use of a conjugate of the studied complex with luminescent ACRIDIN in the incubatory environment. The nonspecific luminescence of the incubatory environment without label was shown to be extremely low: the level of a luminescence of 30-39 RLU is the minimum basic signal and can t significantly influence on results of testing. The starting level of a luminescence in the incubatory environment after supplementation of conjugates of AIMPILA-ACRIDIN or AFP-ACRIDIN is rather high and accounts of 1073714 RLU and 1602017, respectively. In a gleam of the «inverted» pieces of a small intestine the level of a luminescence accounted of 548 and 997 RLU and 425-829 RLU. The obtained data allow to consider the complex AIMPILA in rather low concentration is capable to absorb in a small intestine of rat over the physiologically adequate time that similar to AFP labeled by ACRIDIN.
The objective of the study was to assess the feasibility of using CA -62 marker of epithelial carcinomas for monitoring treatment response and detecting cancer progression or recurrence during chemotherapy.Material and Methods. A 12-month double-blind clinical trial was conducted by two independent groups: clinical oncologists and biochemists, and involved 89 patients with different cancers confirmed by histopathological findings. The other inclusion criteria were: the presence of at least one measurable lesion according to the RECIST criteria, ECOG performance status 0-2 and satisfactory laboratory parameters. The expression of CA -62 cancer marker was measured by immunochemiluminescent assay used for the detection of epithelial carcinomas.Results. The elevated level of CA -62 marker was observed in 76 patients before starting the treatment. After completion chemotherapy, the level of this marker decreased to the normal reference ranges (<4600 U/ml) in 53 % of patients and remained increased in 24 % of patients. Of 24 % of patients with the initial low level of CA -62 marker (1000–4000 U/ml) before treatment, 12 % had no changes in the level of this marker during chemotherapy; however, 5 % of these patients had disease progression and 7 % had stable disease after starting the treatment. In 12 % of patients with an initial low CA -62 level, it increased during chemotherapy, indicating disease progression.Conclusion. The changes in the level of CA -62 marker during chemotherapy in patients with gastric cancer, small-cell lung cancer, colorectal cancer, neuroendocrine cancer and ovarian cancer showed a high correlation (76–100 % depending on the tumor site) with the performance status of the patients according to RECIST criteria. The CA -62 marker was shown to be feasible for monitoring gastric cancer, small-cell lung cancer, colorectal cancer, neuroendocrine cancer and ovarian cancer as well as for assessing the response to chemotherapy.
Аннотация Введение. Способность к всасыванию в тонкой кишке (интернализация) водорастворимых противоопухолевых цитостатиков определяет возможность их перорального применения. Экспресс-метод ex vivo, моделирующий интернализацию веществ в рамках модифицированной методики изолированного «вывернутого» отрезка тонкой кишки крысы с импульсной хемилюминесценцией, адекватен для решения поставленной задачи. Цель исследования-оценка всасывания в организм из тонкой кишки новых водорастворимых противоопухолевых цитостатиков с различными свойствами для доклинического изучения при пероральном введении. Материал и методы. В исследование включены конъюгированные с Акридином (Acridinium NHS Ester, Toronto Research Chemicals, Canada) цитостатики: низкомолекулярный (1) Антрафуран-Акридин (MW 0,8 кДа) и высокомолекулярные (2) Аимпила-Акридин (MW 105 кДа) и (3) L-лизин-α-оксидаза (ЛО-Акридин, MW 122 кДа). Всасывание определено в модифицированной модели изолированного «вывернутого» отрезка тонкой кишки крысы методом импульсной флэш-хемилюминесценции и пересчитано в процентах. Результаты. Показано, что в зависимости от молярной концентрациии от 2500 (1) до 9,2-188 нмоль/л (2, 3) уровень всасывания конъюгированных с Акридином цитостатиков находится в диапазоне от 55 % (1) до 1,7-11 % (2, 3) соответственно. Уровень всасывания конъюгированного Антрафурана (55 %) согласуется с величиной известной эффективной пероральной дозы неконъюгированного цитостатика, которая была в два раза больше, чем эквитерапевтическая парентеральная доза: 100 мг/кг против 50 мг/кг. Заключение. Полученные данные позволяют рассматривать экспресс-метод ex vivo для скрининга возможности доклинического изучения различных водорастворимых противоопухолевых цитостатиков при пероральном введении с прогнозированием стартовой дозы. Метод адекватен тестам in vivo и экономически целесообразен в силу быстрого ответа и малого количества тестируемого агента.
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