A Phase I Study of Oral Uracil-Tegafur Prior to Weekly Intravenous Gemcitabine in Patients with Advanced Pancreatic Cancer

Tanno, Satoshi; Nakano, Yasuhiro; Osanai, Manabu; Koizumi, Kazuya; Izawa, Tsutomu; Habiro, Atsuya; Mizukami, Yusuke; Yanagawa, Nobuyuki; Fujii, Tsuneshi; Okumura, Toshikatsu; Kohgo, Yutaka

doi:10.1159/000092372

Cited by 6 publications

(3 citation statements)

References 19 publications

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“…Aberrant upregulation of this pathway occurs in many human malignancies (9) and is implicated in resistance to radiation preclinically (10,11) and clinically (12)(13)(14). Although radiosensitization was reported with early PI3K inhibitors such as wortmannin and LY294002 (15), these agents had unacceptable pharmacokinetic and toxicity profiles (16) and have now been superseded by novel PI3K inhibitors with superior pharmacologic properties.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of DNA-Dependent Protein Kinase Induces Accelerated Senescence in Irradiated Human Cancer Cells

Azad

Jackson

Cullinane

et al. 2011

Molecular Cancer Research

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DNA-dependent protein kinase (DNA-PK) plays a pivotal role in the repair of DNA double-strand breaks (DSB) and is centrally involved in regulating cellular radiosensitivity. Here, we identify DNA-PK as a key therapeutic target for augmenting accelerated senescence in irradiated human cancer cells. We find that BEZ235, a novel inhibitor of DNA-PK and phosphoinositide 3-kinase (PI3K)/mTOR, abrogates radiation-induced DSB repair resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Importantly, radiation enhancement by BEZ235 coincides with a prominent p53-dependent accelerated senescence phenotype characterized by positive b-galactosidase staining, G 2 -M cell-cycle arrest, enlarged and flattened cellular morphology, and increased p21 expression and senescence-associated cytokine secretion. Because this senescence response to BEZ235 is accompanied by unrepaired DNA DSBs, we examined whether selective targeting of DNA-PK also induces accelerated senescence in irradiated cells. Significantly, we show that specific pharmacologic inhibition of DNA-PK, but not PI3K or mTORC1, delays DSB repair leading to accelerated senescence after radiation. We additionally show that PRKDC knockdown using siRNA promotes a striking accelerated senescence phenotype in irradiated cells comparable with that of BEZ235. Thus, in the context of radiation treatment, our data indicate that inhibition of DNA-PK is sufficient for the induction of accelerated senescence. These results validate DNA-PK as an important therapeutic target in irradiated cancer cells and establish accelerated senescence as a novel mechanism of radiosensitization induced by DNA-PK blockade. Mol Cancer Res; 9(12); 1696-707. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Inhibition of DNA-Dependent Protein Kinase Induces Accelerated Senescence in Irradiated Human Cancer Cells

Azad

Jackson

Cullinane

et al. 2011

Molecular Cancer Research

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“…In a phase II study of UFT, conducted in Japan, UFT exerted antitumor activity against various cancers, with a response rate (RR) of 25% for colorectal cancer, while hematological toxicities were rare and mild [20] . Combinations of UFT with other cytotoxic agents, such as oxaliplatin or gemcitabine, are also being evaluated [21,22] .…”

Section: Introductionmentioning

confidence: 99%

Phase I/II Study of 24-Hour Infusion of Irinotecan Combined with Oral UFT for Metastatic Colorectal Cancer

Sadahiro

Suzuki²,

Maeda³

et al. 2008

Chemotherapy

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Background: To evaluate the efficacy and safety of irinotecan combined with UFT for untreated and pretreated metastatic colorectal cancer. Methods: Escalating doses of irinotecan (80–110 mg/m²) were administered by 24-hour infusion on day 1. UFT was administered orally at 400 mg/m²/day on days 3–7 and 10–14. The treatment cycles were repeated every 2 weeks. Results: In the phase I study, the maximum tolerated dose of irinotecan was 110 mg/m² and the recommended dose for the phase II study was determined to be 100 mg/m². Thirty-five patients including 3 patients at the recommended dose in the phase I study were evaluated in the phase II study. The grade 3/4 toxicities observed were leukopenia, neutropenia, thrombocytopenia and anemia. No grade 3 or more severe nonhematological toxicities were noted. The response rate was 62.9% and the median overall survival 16.7 months. Conclusions: A 24-hour infusion of irinotecan combined with UFT is feasible and active for metastatic colorectal cancer.

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“…We reduced doxifluridine dose, fearing higher toxicity of gemcitabine at a relatively lower dose when FDRI was applied. In a phase I study, oral uracil-tegafur 400 mg/day and gemcitabine 1,000 mg/m 2 in advanced pancreatic cancer was convenient and well tolerated [27] . Actual dose intensity of doxifluridine was 12,600 mg/m 2 /cycle, which was equivalent to 1,417.5 mg/m 2 /cycle of 5-FU.…”

Section: Discussionmentioning

confidence: 99%

Fixed Dose Rate Infusion of Gemcitabine with Oral Doxifluridine and Leucovorin for Advanced Unresectable Pancreatic Cancer: A Phase II Study

Kim

Park²,

Shin³

et al. 2007

Chemotherapy

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The standard beneficial chemotherapy proven for patients with advanced pancreatic cancer is a regimen containing gemcitabine. In the pregemcitabine era, 5-fluorouracil (5-FU) was the standard agent. Oral 5-FU can be added to gemcitabine to improve the efficacy of chemotherapy and to provide better patient convenience. The possibility to improve efficacy of gemcitabine by fixed dose rate infusion (FDRI) was proposed in addition to combining it with 5-FU. We tried a new chemotherapy combining FDRI of gemcitabine with doxifluridine and leucovorin. Eligibility criteria were pathologically proven, chemotherapy-naïve, and metastatic or nonoperable advanced pancreatic cancer. Gemcitabine 1,000 mg/m² was infused over 100 min (days 1, 8 and 15). Doxifluridine 200 mg/m² t.i.d. and leucovorin 15 mg b.i.d. were given orally (days 1–21). Chemotherapy was repeated every 28 days until a patient had received 6 cycles or progression was found. Twenty-nine patients were enrolled from October 2002 to December 2004. A total of 78 cycles were given at a mean of 2.7 cycles per patient. Response could be evaluated in 26 patients. Responses were partial remission in 4/26 patients (15.4%), stable disease in 8/26 (30.8%) and progression in 14/26 (53.8%). All patients progressed except for 2 in partial remission and 2 in stable disease. Toxicities could be assessed in 23 patients. Maximal hematological toxicities greater than grade 2 were leucopenia in 3 patients (11.5%), neutropenia in 2 (7.7%), anemia in 2 (7.7%), thrombocytopenia in 1 (3.8%) and febrile neutropenia in 3 (11.5%). Maximal nonhematological grade 3 or 4 toxicities were asthenia in 1 patient (3.8%), anorexia in 1 (3.8%), vomiting in 1 (3.8%), diarrhea in 2 (7.7%), allergic reaction in 1 (3.8%), hand-foot syndrome in 1 (3.8%) and hyperbilirubinemia in 1 (3.8%). All 29 patients were dead on last follow-up. Median progression-free survival was 3.91 months in 26 evaluable patients and median overall survival was 5.59 months in all patients. Combination chemotherapy including FDRI of gemcitabine seems minimally active for patients with advanced, nonoperable pancreatic cancer. Further research to improve effectiveness of chemotherapy for advanced pancreatic cancer is mandatory.

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A Phase I Study of Oral Uracil-Tegafur Prior to Weekly Intravenous Gemcitabine in Patients with Advanced Pancreatic Cancer

Cited by 6 publications

References 19 publications

Inhibition of DNA-Dependent Protein Kinase Induces Accelerated Senescence in Irradiated Human Cancer Cells

Inhibition of DNA-Dependent Protein Kinase Induces Accelerated Senescence in Irradiated Human Cancer Cells

Phase I/II Study of 24-Hour Infusion of Irinotecan Combined with Oral UFT for Metastatic Colorectal Cancer

Fixed Dose Rate Infusion of Gemcitabine with Oral Doxifluridine and Leucovorin for Advanced Unresectable Pancreatic Cancer: A Phase II Study

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