Эпигаллокатехин и рак

DISCUSSION

Despite extensive data demonstrating that 50% to 70% of patients with asymptomatic, earlier stage CLL will experience progression and require treatment,^2,6,37 such patients are presently managed with observation.³⁸ The phase I data presented here suggests that Polyphenon E may have clinical activity in these patients, and the fact that this treatment is very well tolerated suggests that Polyphenon E merits additional evaluation as a disease-stabilizing agent. With the exception of trisomy 12, the clinical activity observed with Polyphenon E in the present trial did not seem to be influenced by ZAP-70, CD38, or IgVH gene mutation status. This observation suggests that Polyphenon E may have activity in Rai stage 0 to II patients whose prognostic parameters suggest they are at high risk for disease progression.³⁹

The mechanism(s) by which EGCG affects CLL B cells in vivo is unknown. In vitro studies of CLL B cells show that EGCG decreases VEGF receptor phosphorylation and downregulates the expression of MCL-1 and XIAP.³⁰ Indeed, EGCG seems to have greater ability to antagonize MCL-1 than other BCL-2 family member inhibitory compounds in development as CLL therapies including gossypol, apogossypol, and ABT 737.⁴⁰ Other studies suggest that EGCG is a potent inhibitor of BCL-2 at nanomolar concentrations.¹⁸ Although these mechanisms are of particular interest because of the importance of BCL-2 family members,^41–43 and particularly MCL-1,^44–47 in CLL B-cell apoptotic resistance, numerous other mechanisms of action have been proposed for the antitumor effects of EGCG observed in vitro.^9–27,40,48

Because in vitro studies suggest EGCG may have activity against a wide range of human malignancies including prostate, colon, lung, and breast cancer,^49–52 the results of this phase I trial may have relevance for clinical studies of EGCG in other diseases. In this respect, it should be noted that the median age of patients in our study was more than 60 years old and that 70% of participants were men. Although the MTD was not reached in our trial, we chose not to escalate beyond the 2,000 mg twice per day dose level because the high number of capsules required to achieve this dose (10 capsules twice per day) made further dose escalation problematic. It may be possible to escalate beyond this dose level if a more concentrated preparation becomes available. Notably, the plasma levels attained on dose levels 3 to 8 in our study were achieved administering Polyphenon E in the fed state, whereas fasting administration would likely allow patients to achieve similar or higher plasma levels at lower Polyphenon E doses.⁵³

The reason for the wide variation in trough plasma EGCG levels observed in our study is unknown. This variation could relate to differences in absorption when administered with food (eg, total calories, proportion of fat/protein/carbohydrate), metabolism, or protein binding. It is also notable that trough plasma EGCG levels did not clearly relate to the clinical activity of Polyphenon E observed among CLL patients. This observation could indicate other pharmacokinetic parameters (eg, peak levels, area under the curve, and so on) or characteristics of the leukemic clone may relate to the clinical effects of Polyphenon E in CLL patients more strongly than trough plasma levels.

In conclusion, daily oral EGCG in the Polyphenon E preparation was well tolerated at doses up to 2,000 mg twice per day for up to 6 months in patients with asymptomatic Rai stage 0 to II CLL. Declines in ALC and lymphadenopathy during Polyphenon E therapy were observed in the majority of patients. A phase II trial evaluating the efficacy of Polyphenon E (2,000 mg twice per day) in patients with asymptomatic Rai stage 0 to II CLL was initiated in November 2007

Он согласился с тем, что многие противоопухолевые эффекты (-)-эпигаллокатехин галлат (EGCG), которые проводятся при посредничестве различных других эффектов. Мы сообщаем новый Поиск, а именно, antiproliferation потенциал и механизм метилированных-(3")-эпигаллокатехин галлат аналоговый (MethylEGCG) оказывая антиоксидантный эффект, чем EGCG. MethylEGCG ингибировал активность фактора роста эндотелия сосудов (VEGF)-зависело от того, VEGF рецептора 2 и p42/44 MAPK, пролиферации клеток, и пробки в формировании человеческой пуповины сосудистых эндотелиальных клеток (HUVECs) на 1 μ М. даже низкие дозы (1,1 мг/кг в / Я.p. 8.3 мг/кг стр.o.) администрация подавление роста опухоли в xenografted Huh7 гепатомы мышей на 50%. CD31 положительные клетки, визуализированные в кровеносных сосудах, были снижены в опухоли на 18%, что предполагает высокое противоопухолевое действие через ингибирование ангиогенеза. Это исследование показало, что модификация 3" положение метилирование EGCG (MethylEGCG) может снизить рост клеток эффекты при низкой концентрации in vivo.