Phase I Trial of Oral Green Tea Extract in Adult Patients With Solid Tumors

Pisters, Katherine M.W.; Newman, Robert A.; Coldman, Brenda; Shin, Dong M.; Khuri, Fadlo R.; Hong, Waun Ki; Glisson, Bonnie S.; Lee, Jin S.

doi:10.1200/jco.2001.19.6.1830

Cited by 215 publications

(139 citation statements)

References 35 publications

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“…In both studies no major responses occurred and the reported dose-limiting toxicity was related to caffeine (neurological and gastrointestinal effects) [175,176]. In subsequent studies, Jatoi et al [177] and Luo et al [178] have described an antineoplastic activity in terms of biomarkers: diminished PSA levels [177] and decreased urinary 8-hydroxydeoxyguanosine [178] in patients with prostate and hepatic cancer, respectively.…”

Section: Polyphenols and Clinical Trialsmentioning

confidence: 94%

“…In another study, it has been reported that the administration of a green tea extract to patients with histological or cytological proofs of incurable malignancies was safe up to 4.2 g/m 2 once daily or 1.0 g/m 2 three times daily, and in patients with advanced lung cancer a dose of 3 g/m 2 per day was well tolerated [175,176]. In both studies no major responses occurred and the reported dose-limiting toxicity was related to caffeine (neurological and gastrointestinal effects) [175,176].…”

Section: Polyphenols and Clinical Trialsmentioning

confidence: 98%

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Cancer chemoprevention and chemotherapy: Dietary polyphenols and signalling pathways

Ramos¹

2008

Molecular Nutrition Food Res

608

478

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Prevention of cancer through dietary intervention recently has received an increasing interest, and dietary polyphenols have become not only important potential chemopreventive, but also therapeutic, natural agents. Polyphenols have been reported to interfere at the initiation, promotion and progression of cancer. They might lead to the modulation of proteins in diverse pathways and require the integration of different signals for the final chemopreventive or therapeutic effect. Polyphenols have been demonstrated to act on multiple key elements in signal transduction pathways related to cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis and metastasis; however, these molecular mechanisms of action are not completely characterized and many features remain to be elucidated. The aim of this review is to provide insights into the molecular basis of potential chemopreventive and therapeutic activities of dietary polyphenols with emphasis in their ability to control intracellular signalling cascades considered as relevant targets in a cancer preventive approach.

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Section: Polyphenols and Clinical Trialsmentioning

confidence: 94%

Section: Polyphenols and Clinical Trialsmentioning

confidence: 98%

Cancer chemoprevention and chemotherapy: Dietary polyphenols and signalling pathways

Ramos¹

2008

Molecular Nutrition Food Res

608

478

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“…This dose was based in part on previous Phase I testing from Pisters et al 9 Tea was administered in canisters and consisted of pulverized green tea powder as well as sugar, citric acid, and flavoring. Patients were given a 1-gram measuring spoon and were advised to mix a full spoonful of tea directly into either warm or cold water before consuming.…”

Section: Treatment Plan and Test Schedulementioning

confidence: 99%

A Phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma

Jatoi

Ellison²,

Burch

et al. 2003

Cancer

259

146

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BACKGROUNDRecent laboratory and epidemiologic studies have suggested that green tea has antitumor effects in patients with prostate carcinoma. This Phase II trial explored green tea's antineoplastic effects in patients with androgen independent prostate carcinoma.METHODSThis study, which was conducted by the North Central Cancer Treatment Group, evaluated 42 patients who were asymptomatic and had manifested, progressive prostate specific antigen (PSA) elevation with hormone therapy. Continued use of luteinizing hormone‐releasing hormone agonist was permitted; however, patients were ineligible if they had received other treatments for their disease in the preceding 4 weeks or if they had received a long‐acting antiandrogen therapy in the preceding 6 weeks. Patients were instructed to take 6 grams of green tea per day orally in 6 divided doses. Each dose contained 100 calories and 46 mg of caffeine. Patients were monitored monthly for response and toxicity.RESULTSTumor response, defined as a decline ≥ 50% in the baseline PSA value, occurred in a single patient, or 2% of the cohort (95% confidence interval, 1–14%). This one response was not sustained beyond 2 months. At the end of the first month, the median change in the PSA value from baseline for the cohort increased by 43%. Green tea toxicity, usually Grade 1 or 2, occurred in 69% of patients and included nausea, emesis, insomnia, fatigue, diarrhea, abdominal pain, and confusion. However, six episodes of Grade 3 toxicity and one episode of Grade 4 toxicity also occurred, with the latter manifesting as severe confusion.CONCLUSIONSGreen tea carries limited antineoplastic activity, as defined by a decline in PSA levels, among patients with androgen independent prostate carcinoma. Cancer 2003;97:1442–6. © 2003 American Cancer Society.DOI 10.1002/cncr.11200

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“…For example, the doses of GTE given to cancer patients in one Phase I clinical trial were as high as 13.6 g daily. 13 The bioavailability of 1 following long-term GTE intake in large quantities may be significantly greater than the plasma level of 1 achieved from simply drinking tea. Currently, clinical data on plasma levels of ECG (free or 42 As a consequence, the actual quantity of 1 required to activate HIF-1 may be significantly lower if given in the form of GTE, in relation to the activation observed with purified compounds.…”

mentioning

confidence: 99%

“…[10][11][12] Recently, a phase I clinical trial of oral green tea extracts has been completed in adult patients with solid tumors. 13 Major green tea catechins including 1, 2, (−)-epicatechin (EC, 3), and (−)-epigallocatechin (EGC, 4) are believed to be responsible for green tea's cancer chemopreventive activities. However, mixed results have been obtained from epidemiological studies that have examined the connection between green tea and cancer.…”

mentioning

confidence: 99%

Hypoxia-Inducible Factor-1 Activation by (−)-Epicatechin Gallate: Potential Adverse Effects of Cancer Chemoprevention with High-Dose Green Tea Extracts

Zhou

Kim

et al. 2004

J. Nat. Prod.

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Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that induces oxygen-regulated genes in response to reduced oxygen conditions (hypoxia). Expression of the oxygen regulated HIF-1α subunit correlates positively with advanced disease stages and poor prognosis in cancer patients. Green tea catechins are believed to be responsible for the cancer chemopreventive activities of green tea. We found that (−)-epicatechin-3-gallate (ECG, 1), one of the major green tea catechins, strongly activates HIF-1 in T47D human breast carcinoma cells. Among the green tea catechins tested, 1 demonstrated the strongest HIF-1 inducing activity while (−)-epigallocatechin-3-gallate (EGCG, 2), was significantly less active. However, 2 is relatively unstable in the in vitro system studied. Compound 1 also increases the expression of HIF-1 target genes including GLUT-1, VEGF, and CDKN1A. In T47D cells, 1 induces nuclear HIF-1α protein without affecting HIF-1α mRNA. Both the induction of HIF-1α protein and activation of HIF-1 by 1 can be blocked by iron and ascorbate, indicating that 1 may activate HIF-1 through the chelation of iron. These results suggest that intended cancer chemoprevention with high-dose green tea extracts may be compromised, by the ability of tea catechins to promote tumor cell survival pathways associated with HIF-1 activation.Rapid tumor growth often outstrips the ability of blood vessels to supply oxygen and nutrients, leaving many regions inside solid tumors low in oxygen (hypoxia). In cancer patients, the extent of tumor hypoxia correlates positively with advanced disease stages, poor prognosis, and treatment resistance. 1 Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in hypoxia activated gene expression. 2 In tumor cells, HIF-1 activates the transcription of genes involved in anaerobic metabolism, angiogenesis, survival, invasion/metastasis and treatment resistance, thus promoting cellular This study investigates the effects of green tea catechins and related compounds on HIF-1 activity in vitro. Among the compounds tested [1-4, (+)-catechin (5), and gallic acid (6)], only catechins that contain the 3-gallate moiety (1 and 2) activate HIF-1 in a T47D cellbased reporter assay. In addition, 1 inhibits HIF-1 activation under hypoxic conditions. Apart from one hydroxyl group, 1 and 2 are structurally identical. However, 2 is chemically less stable than 1. The focus of this study is the regulation of HIF-1 activity by ECG (1). The pathways and mechanisms involved in HIF-1 activation have been extensively studied. 1,2,9 In the presence of oxygen, the HIF-1α subunit is prolyl hydroxylated, recognized by an E3 ubiquitin ligase complex that contains the von Hippel-Lindau tumor suppressor protein (pVHL), polyubiquitylated, and degraded by the 26S proteosome. [15][16][17] The HIF-1α protein is also asparaginyl hydroxylated to prevent HIF-1 activation. 18 At reduced cellular oxygen levels, inhibition of HIF-1α protein prolyl hydroxylation and degradation leads to an ...

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Phase I Trial of Oral Green Tea Extract in Adult Patients With Solid Tumors

Abstract: A dose of 1.0 g/m(2) tid (equivalent to 7 to 8 Japanese cups [120 mL] of green tea three times daily) is recommended for future studies. The side effects of this preparation of GTE were caffeine related. Oral GTE at the doses studied can be taken safely for at least 6 months.

Cited by 215 publications

References 35 publications

Cancer chemoprevention and chemotherapy: Dietary polyphenols and signalling pathways

Cancer chemoprevention and chemotherapy: Dietary polyphenols and signalling pathways

A Phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma

Hypoxia-Inducible Factor-1 Activation by (−)-Epicatechin Gallate: Potential Adverse Effects of Cancer Chemoprevention with High-Dose Green Tea Extracts

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