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PubMed1999

Dietary compounds that induce cancer preventive phase 2 enzymes activate apoptosis at comparable doses in HT29 colon carcinoma cells.

Dietary agents that induce glutathione S-transferases and related detoxification systems (Phase 2 enzyme inducers) are thought to prevent cancer by enhancing elimination of chemical carcinogens. The present study shows that compounds of this group (benzyl isothiocyanate, allyl sulfide, dimethyl fumarate, butylated hydroxyanisole) activated apoptosis in human colon carcinoma (HT29) cells in culture over the same concentration ranges that elicited increases in enzyme activity (5-25, 25-100, 10-100, 15-60 micromol/L, respectively). Pretreatment of cells with sodium butyrate, an agent that induces HT29 cell differentiation, resulted in parallel increases in Phase 2 enzyme activities and induction of apoptosis in response to the inducers. Cell death characteristics included apoptotic morphological changes, appearance of cells at sub-G1 phase on flow cytometry, caspase activation, DNA fragmentation and TUNEL-positive staining. The results suggest that dietary Phase 2 inducers may protect against cancer by a mechanism distinct from and in addition to that associated with enhanced elimination of carcinogens. If this occurs in vivo, diets high in such compounds could eliminate precancerous cells by apoptosis at time points well after initial exposure to chemical mutagens and carcinogens.

Apoptosis↗

PubMed2001

Phase 2 metabolites of N-hydroxylated amidines (amidoximes): synthesis, in vitro formation by pig hepatocytes, and mutagenicity testing.

A pig hepatocyte culture system was used for phase 2 biotransformation studies in vitro. The viability of the cultured hepatocytes was characterized daily during cultivation by lactate dehydrogenase release into the supernatant and albumin synthesis of the cells. The metabolic activity of the hepatocyte cultures was measured by 7-ethoxycoumarin (ECOD) and 7-ethoxyresorufin O-deethylation (EROD). The viability and metabolic activity of these pig hepatocytes were preserved for several days by culturing the cells in a monolayer culture system. Besides the known reduction of N-hydroxylated benzamidine (benzamidoxime) (2) to benzamidine (1), glucuronidation and, to a much smaller extent, sulfation of 2 to benzamidoxime O-glucuronide (3) and benzamidoxime O-sulfate (4) by cultured pig hepatocytes were found. The analyses were performed using HPLC and LC/MS studies. For unequivocal assignment, the hitherto unknown metabolites 3 and 4 were synthesized and characterized by spectroscopic techniques. Examination of benzamidoxime O-glucuronide and benzamidoxime O-sulfate for mutagenicity by means of the Ames test revealed that both phase 2 conjugates have no mutagenic effects in the TA98 and TA100 strains. So the phase 2 conjugation of benzamidoxime is significant in terms of detoxification.

Amidines↗

PubMed1995

Chemoprotection against cancer by phase 2 enzyme induction.

Mammalian cells have evolved elaborate mechanisms for protection against the toxic and neoplastic effects of electrophilic metabolites of carcinogens and reactive oxygen species. Phase 2 enzymes (e.g. glutathione transferase, NAD(P)H:quinone reductase, UDP-glucuronosyltransferases) and high intracellular levels of glutathione play a prominent role in providing such protection. Phase 2 enzymes are transcriptionally induced by low concentrations of a wide variety of chemical agents and such induction blocks chemical carcinogenesis. The inducers belong to many chemical classes including phenolic antioxidants. Michael reaction acceptors, isothiocyanates, 1,2-dithiole-3-thiones, trivalent arsenicals, HgCl2 and organomercurials, hydroperoxides, and vicinal dimercaptans. Induction by all classes of inducers involves the antioxidant/electrophile response element (ARE/EpRE). Inducers are widely, but unequally, distributed among edible plants. Search for such inducer activity in broccoli led to the isolation of sulforaphane, an isothiocyanate that is a very potent Phase 2 enzyme inducer and blocks mammary tumor formation in rats.

Animals↗

PubMed2000

Novobiocin in combination with high-dose chemotherapy for the treatment of advanced breast cancer: a phase 2 study.

We conducted the first phase 2 and pharmacologic study to evaluate the combination of novobiocin (a coumeromycin antibiotic that has been shown to augment alkylating agent cytotoxicity in experimental models) and high-dose cyclophosphamide and thiotepa followed by autologous marrow support in women with chemosensitive advanced breast cancer. Its aims were (1) to determine progression-free survival (PFS) and overall survival (OS), (2) to evaluate the pharmacokinetics of cyclophosphamide and thiotepa, and (3) to measure the ability of novobiocin to reverse alkylator drug resistance in vitro. Forty-one women with chemotherapy-responsive advanced breast cancer received cyclophosphamide (4 g/m2) for peripheral blood stem cell mobilization (treatment 1) followed by high-dose cyclophosphamide (1.5 g/m2 per day for 4 days), thiotepa (200 mg/m2 per day for 4 days), and novobiocin (4 g/day orally for 7 days) (treatment 2) and autologous marrow support. The median PFS was 10 months (range, 0.2-70.6 months) and OS, 21.5 months (range, 0.2-70.6 months). There was no statistically significant relationship between PFS or OS and area-under-the-curve values of cyclophosphamide, thiotepa, or 4-hydroxycyclophosphamide. Patient plasma samples (n = 12) obtained during novobiocin therapy were able to reverse alkylator drug resistance in an in vitro colony-forming assay. Correlative laboratory studies in an in vitro model system demonstrated that patient plasma after novobiocin treatment resulted in the magnitude of resistance reversal that had been predicted by prior preclinical experiments. Clinically, however, this activity of novobiocin did not translate into a substantial increase in PFS or OS compared with historical controls treated with high-dose alkylator therapy alone.

Adult↗

PubMed2001

Total intracellular accumulation levels of dietary isothiocyanates determine their activity in elevation of cellular glutathione and induction of Phase 2 detoxification enzymes.

Many dietary isothiocyanates (ITCs) have shown cancer chemoprotective activity in animal models. Isothiocyanates rapidly accumulate in cells of various types as glutathione conjugates, and the total intracellular accumulation levels of ITCs (area under time-concentration curve; AUC) were critical for their Phase 2 enzyme inducer activities in murine hepatoma Hepa 1c1c7 cells. Induction of Phase 2 detoxification enzymes is recognized as a major cellular defense against carcinogens and other toxic agents. In order to further define the importance of intracellular AUC of ITCs in stimulating cellular detoxification functions, we have compared the intracellular AUCs and the inducer activities of four common dietary ITCs, allyl-ITC, benzyl-ITC, phenethyl-ITC and sulforaphane [1-isothiocyanato-(4R,S)-(methylsulfinyl)butane], in mouse skin papilloma (PE) cells. When PE cells were incubated with 5 microM of each ITC for 24 h, significant elevations of glutathione content (1.8-4.3-fold), quinone reductase activity (2.1-5.4-fold) and glutathione transferase activity (0.8-1.5-fold) were observed. These elevations were closely correlated with the AUCs of the ITCs. Increasing intracellular AUC of a weaker ITC by multiple dosing also increased its inducer activity. Further studies revealed that the AUC-dependent elevation of the above elements were mediated by the DNA regulatory element EpRE/ARE. In human HepG2 cells, which were stably transfected with a reporter construct under EpRE/ARE control, the intracellular AUC of the four ITCs closely correlated with the levels of reporter gene product (green fluorescent protein). These results showed that cellular accumulation levels of ITCs determine their activity in inducing cellular detoxification capacity and suggested that the intracellular AUC might be a valuable biomarker of the Phase 2 enzyme inducer activity of ITCs.

Animals↗

PubMed2003

[Analysis of the polymorphic alleles of genes encoding phase 1 and phase 2 detoxication enzymes in patients with endometriosis].

Polymorphysms of the three genes encoding phase 1 (CYP1A1, mEPH1, and CYP2E2) and the three genes encoding phase 2 (NAT2, GSTM1, and GSTT1) xenobiotic detoxication enzymes were typed by use of PCR in 74 patients with extragenital endometriosis. Distribution of the CYP1A1, mEPHX1, CYP2E1, NAT2, and GSTM1 polymorphic alleles in the patient group corresponded to that in the control group. At the same time, functionally defective genotypes GSTM1 0/0, NAT2 S/S; GSTM1 0/0, GSTT1 0/0; and GSTT1 0/0, NAT2 S/S were three, four and eight times more frequent among the patients than in healthy individuals. This observation suggests the existence of a distinct association between the functionally defective alleles of the phase 2 xenobiotic detoxication and endometriosis. Possible mechanisms underlying this association are discussed. It is suggested that typing of the NAT2, GSTM1, and GSTT1 genes can be useful for the assessment of the predisposition to endometriosis.

Alleles↗

PubMed2002

Amelioration of experimental allergic encephalitis (EAE) through phase 2 enzyme induction.

The multiple sclerosis (MS) lesion is characterized by an inflammatory cell mediated attack on white matter. Oxidative stress appears to play a role in the onset and progression of MS. We reasoned that decreasing oxidative stress might ameliorate MS. One way of decreasing oxidative stress is to induce phase 2 enzymes. The model chosen to test this hypothesis was experimental allergenic encephalomyelitis (EAE) induced in the Lewis rat. The 26 animals were placed into two groups: 1) those on normal rat chow, 2) those on rat chow containing 250 mumoles t-butylhydroxyanisole (BHA)/kg. After 2 weeks, animals were administered 100 micrograms guinea pig myelin basic protein and examined daily in a blinded fashion. Twenty-nine days later, animals were sacrificed, blood collected for glutathione (GSH) measurements and tissues collected for histology. Six of the 13 control chow animals developed hindlimb weakness or paralysis while 5 developed tail weakness only. Only 1 BHA fed animal exhibited symptoms--hindlimb weakness. Clinical symptoms correlated well with the extent of perivascular lymphocyte infiltration. Animals with BHA in the diet had 20% higher red cell GSH indicting induction of phase 2 enzymes. We conclude that dietary phase 2 enzyme inducers should be examined for their ability to ameliorate MS.

Animals↗

PubMedDate not supplied

Basal cell adenoma of the parotid gland: characteristics of 2-phase helical computed tomography and magnetic resonance imaging.

OBJECTIVE: The goal of this study was to report the radiologic characteristics of basal cell adenoma of the parotid gland, which is a relatively rare neoplasm. METHODS: A radiology and otolaryngology specialist reviewed the 2-phase helical computed tomography (CT) (n = 6) and/or magnetic resonance (MR) imaging (n = 2) scans of 7 patients with basal cell adenoma. The authors evaluated the imaging characteristics, including tumor size, location, contour and margin, internal density or signal intensity, contrast enhancement pattern, and presence of calcification. The imaging features were then analyzed and correlated with the pathologic findings. RESULTS: All the tumors presented as small (less than 3 cm), well-encapsulated, round or oval masses on CT or MR imaging. On the 2-phase CT scan, the mostly solid-looking tumors (n = 4) showed marked contrast enhancement on the early phase, and there was a subsequent decrease in attenuation on the delayed phase. These tumors were classified as the solid subtype on histologic examination. Meanwhile, the tumors with large cystic areas (n = 2) showed gradual and additional enhancement on the delayed phase and were classified as the tubular or trabecular subtype on pathologic evaluation. There were small spots of low attenuation in the tumors of the solid subtype, which were proved to be intratumoral microcysts in the pathologic correlation. Calcification was found in a tumor. CONCLUSIONS: Basal cell adenomas of the parotid gland present as small well-marginated tumors and appear as masses with central large cysts or solid masses with microcysts on CT and MR imaging scans. Basal cell adenomas of the parotid gland had at least 2 different enhancement patterns on the 2-phase helical CT scans, and the enhancement patterns and imaging architecture were related to the histologic subtype of the tumors.

Adenoma↗

PubMed2004

Potent induction of cellular antioxidants and phase 2 enzymes by resveratrol in cardiomyocytes: protection against oxidative and electrophilic injury.

Resveratrol is known to be protective against oxidative cardiovascular disorders. However, the underlying mechanisms remain unclear. This study was undertaken to determine if resveratrol could increase endogenous antioxidants and phase 2 enzymes in cardiomyocytes, and if such increased cellular defenses could provide protection against oxidative and electrophilic cell injury. Incubation of cardiac H9C2 cells with low micromolar resveratrol resulted in a significant induction of a scope of cellular antioxidants and phase 2 enzymes in a concentration- and/or time-dependent fashion. To investigate the protective effects of the resveratrol-induced cellular defenses on oxidative and electrophilic cell injury, H9C2 cells were first incubated with resveratrol, and then exposed to xanthine oxidase (XO)/xanthine, 4-hydroxy-2-nonenal or doxorubicin. We observed that resveratrol pretreatment afforded a marked protection against the above agent-mediated cytotoxicity in H9C2 cells. Moreover, the resveratrol pretreatment led to a great reduction in XO/xanthine-induced intracellular accumulation of ROS. Taken together, this study demonstrates that resveratrol induces antioxidants and phase 2 enzymes in cardiomyocytes, which is accompanied by increased resistance to oxidative and electrophilic cell injury.

Aldehydes↗

PubMed2003

The OECD program to validate the rat uterotrophic bioassay. Phase 2: coded single-dose studies.

The Organisation for Economic Co-operation and Development has completed phase 2 of an international validation program for the rodent uterotrophic bioassay. This portion of phase 2 assessed the reproducibility of the assay with a battery of positive and negative test substances. Positive agonists of the estrogen receptor included the potent reference estrogen 17-ethinyl estradiol (EE), and the weak estrogen agonists bisphenol A, genistein, methoxychlor, nonylphenol, and o,p -DDT. The negative test substance or nonagonist was n-dibutylphthalate. The test substances were coded, and prescribed doses of each test substance were administered in 16 laboratories. Two versions of the uterotrophic assay, the intact immature and the adult ovariectomized female rat, were tested and compared using four standardized protocols covering both sc and po administration. Assay reproducibility was compared using a) EE doses identical to those used in phase 1 and in parallel dose-response studies, b) single doses of the weak agonists identical to one of five doses from the dose-response studies, and c) a single dose of the negative test substance. The results were reproducible and in agreement both within individual laboratories and across the participating laboratories for the same test substance and protocol. The few exceptions are examined in detail. The reproducibility was achieved despite a variety of different experimental conditions (e.g., variations in animal strain, diet, housing protocol, bedding, vehicle, animal age). In conclusion, both versions of the uterotrophic bioassay and all protocols appear robust, reproducible, and transferable across laboratories and able to detect weak estrogen agonists. These results will be submitted along with other data for independent peer review to provide support for the validation of the uterotrophic bioassay.

Animal Feed↗

PubMed2005

The phase 2 enzyme inducers ethacrynic acid, DL-sulforaphane, and oltipraz inhibit lipopolysaccharide-induced high-mobility group box 1 secretion by RAW 264.7 cells.

The diuretic ethacrynic acid (EA) has been shown to inhibit signaling by the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB). Accordingly, we sought to determine whether this compound is capable of inhibiting the release of cytokines [interleukin (IL)-6 and IL-10] and NO from RAW 264.7 murine macrophage-like cells stimulated with lipopolysaccharide (LPS). Additionally, we sought to determine whether EA can inhibit secretion of high-mobility group box 1 (HMGB1), a nuclear protein that is secreted by immunostimulated macrophages and functions in the extracellular milieu as a proinflammatory mediator. In a concentration-dependent manner, EA inhibited secretion of IL-6, IL-10, nitric oxide, and HMGB1. As expected, EA inhibited NF-kappaB DNA binding in LPS-stimulated RAW 264.7 cells. Treating these cells with pyrrolidine dithiocarbamate, SN50 (amino acid sequence AAVALLPAVLLALLAPVQRKRQKLMP) or 5-(thien-3-yl)-3-aminothiophene-2-carboxamide (SC-514) also inhibited LPS-induced NF-kappaB DNA binding, but these compounds failed to inhibit LPS-induced HMGB1 secretion. These findings suggested that inhibition of HMGB1 secretion by EA might occur via a mechanism unrelated to the NF-kappaB signaling pathway. Because EA is an electrophilic compound that is known to be capable of inducing expression of so-called phase 2 proteins, we sought to determine whether two other phase 2 enzyme inducers, oltipraz and DL-sulforaphane, also are capable of inhibiting HMGB1 release from immunostimulated macrophages. Incubating RAW 264.7 cells with either oltipraz or DL-sulforaphane inhibited LPS-induced HMGB1 secretion. Moreover, both EA and DL-sulforaphane inhibited relocalization of nuclear HMGB1 into the cytoplasm of LPS-stimulated RAW 264.7 cells. These data suggest that phase 2 inducers may exert anti-inflammatory effects by inhibiting secretion of the cytokine-like nuclear protein HMGB1.

Active Transport, Cell Nucleus↗

PubMed2004

Polyozellin isolated from Polyozellus multiplex induces phase 2 enzymes in mouse hepatoma cells and differentiation in human myeloid leukaemic cell lines.

Induction of cellular phase 2 detoxifying enzymes is associated with cancer preventive potential. Quinone reductase (QR) has been used as a prototype for anticarcinogenic phase 2 enzymes because of its widespread distribution in mammalian systems, large amplitude of inducer response, and ease of measurement in murine hepatoma cells. Methanol extract of Polyozellus multiplex, which shows a strong QR induction potential, was subjected to bioassay-guided fractionation, and polyozellin (PM1) appeared to be a major active component. In in vitro cultured cells (hepa1c1c7 and BPRc1 cells), polyozellin enhanced QR, glutathione S-transferase (GST) activities, and glutathione (GSH) content in a dose-dependent manner. The compound also significantly promoted differentiation of HL-60 human promyelocytic emia cells. In conclusion, polyozellin deserves further in vivo study to evaluate its potential as a cancer preventive agent.

Agaricales↗

PubMed2004

Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers.

Induction of a family of phase 2 genes encoding for proteins that protect against the damage of electrophiles and reactive oxygen intermediates is potentially a major strategy for reducing the risk of cancer and chronic degenerative diseases. Many phase 2 genes are regulated by upstream antioxidant response elements (ARE) that are targets of the leucine zipper transcription factor Nrf2. Under basal conditions, Nrf2 resides mainly in the cytoplasm bound to its cysteine-rich, Kelch domain-containing partner Keap1, which is itself anchored to the actin cytoskeleton and represses Nrf2 activity. Inducers disrupt the Keap1-Nrf2 complex by modifying two (C273 and C288) of the 25 cysteine residues of Keap1. The critical role of C273 and C288 was established by (i) their high reactivity when purified recombinant Keap1 was treated with dexamethasone mesylate and the dexamethasone-modified tryptic peptides were analyzed by mass spectrometry, and (ii) transfection of keap1 and nrf2 gene-deficient mouse embryonic fibroblasts with constructs expressing cysteine to alanine mutants of Keap1, and measurement of the ability of cotransfected Nrf2 to repress an ARE-luciferase reporter. Reaction of Keap1 with inducers results in formation of intermolecular disulfide bridges, probably between C273 of one Keap1 molecule and C288 of a second. Evidence for formation of such dimers was obtained by 2D PAGE of extracts of cells treated with inducers, and by the demonstration that whereas C273A and C288A mutants of Keap1 alone could not repress Nrf2 activation of the ARE-luciferase reporter, an equal mixture of these mutant constructs restored repressor activity.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Phase 2 trial of carboplatin, paclitaxel, and irinotecan in ovarian, fallopian tube, and primary peritoneal cancers.

OBJECTIVE: Our goal in this nonrandomized phase 2 trial was to evaluate the toxicity and obtain preliminary data on the potential efficacy of a novel three-drug combination regimen (carboplatin-paclitaxel-irinotecan) when employed as initial therapy of advanced ovarian cancer or as second-line treatment in the setting of a prolonged (>or=12 months) treatment-free interval. METHODS: Patients with a histologically confirmed diagnosis of advanced ovarian cancer, primary adenocarcinoma of the peritoneum, or fallopian tube cancer were enrolled in the study. Patients received carboplatin (AUC 5), paclitaxel (150 mg/m(2) over 3 h), and irinotecan (100 mg/m(2) over 90 min). The three-drug combination was initially administered on an every 21-day schedule, but due to toxicity was subsequently changed to a 28-day program. RESULTS: A total of 30 patients were enrolled into this phase 2 trial. Twenty-three patients were chemotherapy naive, while 7 had received prior chemotherapy. Seventeen patients completed all six cycles of treatment. Eight patients (27%) were removed from the study after a median of three cycles due to toxicities. Seventeen patients (57%) experienced grade 4 neutropenia, with three individuals requiring hospitalization for neutropenic fever and dehydration. Grades 3 and 4 thrombocytopenia were experienced by three patients each. The principal nonhematologic toxicities were diarrhea (grade 3: three patients) and fatigue. The overall objective clinical response rate was 83%. CONCLUSIONS: The combination of carboplatin-paclitaxel-irinotecan can be administered to women with advanced ovarian cancer with significant, but overall acceptable toxicity. Modification of the regimen from a 3-week to a 4-week schedule permits a greater percentage of patients to complete the program without experiencing excessive toxicity. The overall objective response rate observed in this trial is comparable to other combination regimens employed in this setting. Defining a place for this three-drug program in the standard management of ovarian cancer will require the conduct of an appropriately designed randomized trial.

Adult↗

PubMed2002

Pinostrobin from honey and Thai ginger (Boesenbergia pandurata): a potent flavonoid inducer of mammalian phase 2 chemoprotective and antioxidant enzymes.

Over 60 different samples comprising 35 distinct honeys were evaluated for their ability to induce mammalian phase 2 detoxication enzymes using a microtiter plate assay of quinone reductase (QR) induction with murine hepatoma cells in microtiter plates. This assay has been used extensively to identify and isolate a variety of natural and synthetic inducers from plants. All 35 honeys examined induced elevations of mammalian QR activity ranging from 153 to 2155 units/g with a mean of 630 and a median of 417 units/g. The concentrations for doubling the QR activity (CD) of certain of the prominent flavonoids found in honey were also assessed (pinostrobin, 0.5 microM; pinocembrin, 110 microM; chrysin, 25 microM) and compared to those of related, more commonly described flavonoids such as quercetin (2.7 microM) and myricetin (58 microM). On the basis of the extremely high QR inducing potency of one of these compounds, pinostrobin (5-hydroxy-7-methoxyflavanone), a bioassay-guided search was conducted which revealed a dietary source of pinostrobin, Boesenbergia pandurata (fingerroot), with extraordinarily high ability to induce mammalian phase 2 detoxication enzymes. Although the QR inducing activity of buckwheat honeys was 2155 +/- 951 units/g (n = 8 samples), which is less than 10% of the average values obtained from fresh broccoli, the potency of fingerroot rhizomes (ca. 110,000 units/g) is even higher than that of broccoli and the potencies of fingerroot oil and powdered rhizome (ca. 500,000 units/g) rival that of broccoli sprouts.

Anticarcinogenic Agents↗

PubMed2001

Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.

This report of a phase 2 trial of thalidomide (THAL) (200 mg/d; 200 mg increment every 2 weeks to 800 mg) for 169 patients with advanced myeloma (MM) (abnormal cytogenetics (CG), 67%; prior autotransplant, 76%) extends earlier results in 84 patients. A 25% myeloma protein reduction was obtained in 37% of patients (50% reduction in 30% of patients; near-complete or complete remission in 14%) and was more frequent with low plasma cell labeling index (PCLI) (below 0.5%) and normal CG. Two-year event-free and overall survival rates were 20% +/- 6% and 48% +/- 6%, respectively, and these were superior with normal CG, PCLI of less than 0.5%, and beta(2)-microglobulin of 3 mg/L. Response rates were higher and survival was longer especially in high-risk patients given more than 42 g THAL in 3 months (median cumulative dose) (landmark analysis); this supports a THAL dose-response effect in advanced MM.

Angiogenesis Inhibitors↗

PubMed1997

Two models of grammar facilitation in children with language impairments: phase 2.

Fey, Cleave, Long and Hughes (1993) demonstrated the effectiveness of two 5-month interventions for preschoolers with problems in expressive grammar. This article reports the results of an additional 5-month intervention phase for 18 of the original participants. Results indicated that although participants improved during Phase 2, improvements generally were not as strong as those noted for Phase 1. Gains were larger and more consistent for children who received the relatively costly clinician-administered approach than for those who received a less expensive parent-administered intervention. The parent intervention was successful in helping parents to use sentence recasts, and especially so for parents of children at relatively early stages of grammatical development, Finally, children who were dismissed after a highly successful treatment Phase 1 generally exhibited no gains over the no-treatment Phase 2.

Child↗

PubMed2005

GNOSIS: guidelines for neuro-oncology: standards for investigational studies-reporting of phase 1 and phase 2 clinical trials.

We present guidelines to standardize the reporting of phase 1 and phase 2 neuro-oncology trials. The guidelines are also intended to assist with accurate interpretation of results from these trials, to facilitate the peer-review process, and to expedite the publication of important and accurate manuscripts. Our guidelines are summarized in a checklist format that can be used as a framework from which to construct a phase 1 or 2 clinical trial.

Clinical Trials, Phase I as Topic↗