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Featured researches published by Kenzo Iizuka.


Drug Design Development and Therapy | 2018

Anticancer activity of the intraperitoneal-delivered DFP-10825, the cationic liposome-conjugated RNAi molecule targeting thymidylate synthase, on peritoneal disseminated ovarian cancer xenograft model

Kenzo Iizuka; Cheng Jin; Kokoro Eshima; Mei Hua Hong; Kiyoshi Eshima; Masakazu Fukushima

Introduction Peritoneal disseminated ovarian cancer is one of the most difficult cancers to treat with conventional anti-cancer drugs and the treatment options are very limited, although an intraperitoneal (ip) paclitaxel has shown some clinical benefit. Therefore, treatment of peritoneal disseminated ovarian cancer is a highly unmet medical need and it is urgent to develop a new ip delivered drug regulating the fast DNA synthesis. Methods We developed a unique RNAi molecule consisting of shRNA against the thymidylate synthase (TS) and a cationic liposome (DFP-10825) and tested its antitumor activity and PK profile in peritoneally disseminated human ovarian cancer ascites models by the luciferase gene-transfected SCID mice. DFP-10825 alone, paclitaxel alone or combination with DFP-10825 and paclitaxel were administered in an ip route to the tumor-bearing mice. The TS expression level was measured by conventional RT-PCR. The anti-tumor activity and host survival benefit by DFP-10825 treatment on tumor-bearing mice were observed as resulting from the specific TS mRNA knock-down in tumors. Results DFP-10825 alone significantly suppressed the growth of SKOV3-luc tumore ascites cells and further extended the survival time of these tumor-bearing mice. Combination with the ip paclitaxel augmented the antitumor efficacy of DFP-10825 and significantly prolonged the survival time in the tumor-bearing mice. Short-hairpin RNA for TS (TS shRNA) levels derived from DFP-10825 in the ascetic fluid were maintained at a nM range across 24 hours but not detected in the plasma, suggesting that TS shRNA is relatively stable in the peritoneal cavity, to be able to exert its anti-tumor activity, but not in blood stream, indicating little or no systemic effect. Conclusion Collectively, the ip delivery of DFP-10825, TS shRNA conjugated with cationic liposome, shows a favorable antitumor activity without systemic adverse events via the stable localization of TS shRNA for a sufficient time and concentration in the peritoneal cavity of the peritoneally disseminated human ovarian cancer-bearing mice.


Drug Design Development and Therapy | 2017

Development of new promising antimetabolite, DFP-11207 with self-controlled toxicity in rodents

Masakazu Fukushima; Kenzo Iizuka; Cheng Jin; Chung Zhang; Mei Hong; Kiyoshi Eshima

To reduce 5-fluorouracil (5-FU)-induced serious toxicities without loss of antitumor activity, we have developed DFP-11207, a novel fluoropyrimidine, which consists of 1-ethoxymethyl-5-fluorouracil (EM-FU; a precursor form of 5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP; an inhibitor of 5-FU degradation), and citrazinic acid (CTA; an inhibitor of 5-FU phosphorylation). In vitro studies of DFP-11207 indicated that it strongly inhibited the degradation of 5-FU by dihydropyrimidine dehydrogenase (DPD) in homogenates of the rat liver, and also inhibited the phosphorylation of 5-FU by orotate phosphoribosyltransferase (OPRT) in tumor tissues in a similar magnitude of potency by CDHP and CTA, respectively. Especially, DFP-11207 inhibited the intracellular phosphorylation of 5-FU in tumor cells in a dose-dependent manner whereas CTA alone did not protect intracellular 5-FU phosphorylation. These results postulate that DFP-11207 rapidly entered into the cell and the free CTA produced from DFP-11207 inhibited the phosphorylation of 5-FU in the cell. Furthermore, following oral administration of DFP-11207, CTA was found to be highly retained in the gastrointestinal (GI) tract compared to other tissues in rats. Interestingly, EM-FU, the prodrug of 5-FU was found to specifically produce 5-FU by various species of liver microsomes. When DFP-11207 was administered to rats, the plasma level of 5-FU was persisted for a long-time with lower Cmax and longer half-life than that from other 5-FU prodrugs. The antitumor activity of DFP-11207 was evaluated in human tumor xenografts in nude rats and found that DFP-11207 showed an antitumor activity in a dose-dependent fashion and its efficacy is equivalent to reference 5-FU drugs. In striking contrast, DFP-11207 manifested no or less 5-FU-related toxicities, such as a decrease in body weights, GI injury, and myelosuppression, especially thrombocytopenia. Taken together, the preclinical evaluation of DFP-11207 strongly indicates that DFP-11207 be a potential new version of the oral fluoropyrimidine prodrug for further clinical development.


Cancer Research | 2017

Abstract 2192: DFP-10825 IP delivery provides a new effective treatment option to peritoneal-disseminated cancers

Cheng Jin; Kenzo Iizuka; Kokoro Eshima; Masakazu Fukushima; Tatsuhiro Ishida; Cheng-long Huang; Hiromi Wada; Kiyoshi Eshima

Objective: Peritoneal disseminated ovarian and pancreatic cancers are the most difficult to be treated with conventional cytotoxic or molecular targeted drugs. The treatment option is very limited although an intraperitoneal (IP) paclitaxel has been available and shown to improve a prognosis in patients. Therefore, it is urgent to develop a new IP chemotherapeutic drug regulating the fast DNA synthesis in peritoneal disseminated tumors originated commonly from the ovary, pancreas and stomach. We have developed a unique RNAi molecule consisting of shRNA (55-mer) against TS and a cationic liposome (DFP-10825) and tested its anti-tumor activity and PK profile in peritoneal disseminated ascetic tumor models. Methods: We developed luciferase gene-transfected ovarian cancer (SKOV3-luc) and pancreatic cancer (PANC-1-luc) models in mice. After IP injection of 5x106 cells, DFP-10825 containing 20 µg TS shRNA (20 mg/mouse) was administered in an IP route (q3d x 4) to the tumor-bearing mice. In combination therapy, paclitaxel (10 mg/kg) was also IP administered to SKOV3-luc model to which the treatment was performed in the same schedule. The anti-tumor effect was assessed by measuring luciferase activity and tumor volume. Furthermore, the TS expression level in both ascetic tumor cells and solid tumors was measured by conventional RT-PCR. For PK study with DFP-10825 (especially TS shRNA), total RNAs were isolated at various time points from ascetic tumor cells and disseminated SKOV3-luc solid tumor models treated with DFP-10825 and TS shRNA levels were determined by Stem-loop RT-PCR. Results: IP DFP-10825 delivery significantly suppressed the growth of ascetic SKOV3-luc and PANC-1-luc tumor cells and extended the survival time of these tumor-bearing mice compared with that of control group. Combination with the IP paclitaxel augmented the efficacy of DFP-10825. After the IP administration, TS shRNA levels derived from DFP-10825 in ascetic fluid were maintained at nM range (0.7 - 4.3-nM) across 24 hours but not detected (below 5 pM) in the plasma, suggesting that TS shRNA be relatively stable in the peritoneal cavity to be able to exert its anti-tumor activity but not in blood. Also, TS expression (TS mRNA) in ascetic tumor cells was significantly suppressed, supporting the notion that the anti-tumor activity and host survival benefit by DFP-10825 in tumor-bearing mice are through MOA to knock down the TS level in tumors specifically. Conclusion: IP administration of newly developed DFP-10825, the TS shRNA conjugated with cationic liposome is localized stably in the peritoneal cavity and provides a new effective treatment option to the intractable peritoneal disseminated ovarian and pancreatic cancers without any systemic adverse events. Citation Format: Cheng Jin, Kenzo Iizuka, Kokoro Eshima, Masakazu Fukushima, Tatsuhiro Ishida, Cheng-Long Huang, Hiromi Wada, Kiyoshi Eshima. DFP-10825 IP delivery provides a new effective treatment option to peritoneal-disseminated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2192. doi:10.1158/1538-7445.AM2017-2192


Cancer Research | 2017

Abstract 5099: Development of novel antimetabolite, DFP-11207, with self-toxicity protection and its promising preclinical and clinical profiles

Masakazu Fukushima; Kenzo Iizuka; Kokoro Eshima; Chung Zhang; Cheng Jin; Kiyoshi Eshima; Jaffer A. Ajani

Background: For over 50 years, 5-fluorouracil (5-FU) has played a critical role in the systemic chemotherapy of various gastrointestinal cancers including gastric, colorectal and pancreatic cancer which are the leading causes of cancer death globally. Although systemic cytotoxics such as 5-FU can modestly prolong overall survival in the adjuvant and advanced settings, but at the cost of unpleasant toxicities. Therefore better drug formulations are desirable. Methods: To this end, we developed a new conceptual fluoropyrimidine, DFP-11207 that is engineered to reduce toxicity without loss of antitumor activity as well in addition to providing sustained concentrations of the active anticancer moiety. DFP-11207 contains three components in one formulation: 1-ethoxymethyl-5-fluorouracil (EM-FU) as a prodrug of 5-FU, 5-chloro-2,4-dihyroxypyridine (CDHP) as a potent inhibitor of 5-FU degradation and cytrazinic acid (CTA) as a gastrointestinal regulator of 5-FU phosphorylation. Results: In in vitro metabolism studies using cell-free extracts from plasma, liver and tumors or intact tumor cells, DFP-11207 was rapidly hydrolyzed to 3 components and subsequently EM-FU was specifically converted to 5-FU by liver microsomes, and CDHP and CTA strongly inhibited 5-FU degradation and phosphorylation, respectively. Following consecutive oral administration to human tumor-bearing nude rats, DFP-11207 attained favorable antitumor efficacy and long-sustained PK profiles with lack of GI- and myelo-toxicities. Next, in investigational clinical study in patients with solid tumors, 12 patients were treated at 8 unique dose levels of DFP-11207, ranging from 40 to 440mg/m2/day by each 1 pt. MTD and RD of daily and 28-day consecutive DFP-11207 was found to be 440 (n=2) and 330 mg/m2 (n=6), respectively. The main AEs were nausea,, anemia, neutropenia, febrile neutropenia but these events were very mild, and no thrombocytopenia was observed as expected. Furthermore, review of the preliminary PK data, DFP-11207 at 330 mg/m2 resulted in a desirable low but efficacious (~15- 30 ng/ml) steady-state plasma concentration of 5-FU. Interestingly, some of patients heavily treated with therapeutic drugs had a stable-disease for long periods. Conclusion: Our preclinical and early clinical data with DFP-11207 suggest that it’s a promising compound for the treatment of gastrointestinal cancers and can overcome the shortcomings of all other oral fluoropyrimidines. Citation Format: Masakazu Fukushima, Kenzo Iizuka, Kokoro Eshima, Chung Zhang, Cheng Jin, Kiyoshi Eshima, Jaffer Ajani. Development of novel antimetabolite, DFP-11207, with self-toxicity protection and its promising preclinical and clinical profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5099. doi:10.1158/1538-7445.AM2017-5099


Blood | 2016

Phase I/II Study of DFP-10917 in Relapsed/Refractory AML Demonstrates Efficacy and Safety Profile Suitable for Phase III Study

Hagop M. Kantarjian; Elias Jabbour; Guillermo Garcia-Manero; Tapan Kadia; Courtney D. DiNardo; Naval Daver; Gautam Borthakur; Nitin Jain; Jane Waukau; Monica Kwari; Barry Douglas Anderson; Kenzo Iizuka; Cheng Jin; Chun Zhang; Farhad Ravandi; William Plunkett


International Journal of Oncology | 2018

Analysis of the prolonged infusion of DFP-10917, a deoxycytidine analog, as a therapeutic strategy for the treatment of human tumor xenografts in vivo

Kenzo Iizuka; Chun Zhang; Kokoro Eshima; Cheng Jin; Kiyoshi Eshima; Masakazu Fukushima


Journal of Clinical Oncology | 2017

First report of a phase I/II study of DFP-10917, a nucleoside analog, given by continuous infusion (CI) in patients (pts) with relapsed or refractory acute leukemia.

Hagop M. Kantarjian; Elias Jabbour; Guillermo Garcia-Manero; Tapan Kadia; Courtney D. DiNardo; Naval Daver; Gautam Borthakur; Nitin Jain; Jane Waukau; Monica Kwari; Barry Anderson; Kenzo Iizuka; Cheng Jin; William Plunkett


Investigational New Drugs | 2018

Phase II study of DFP-10917, a deoxycytidine analog, given by 14-day continuous intravenous infusion for chemotherapy-refractory advanced colorectal cancer

Amir Mehrvarz Sarshekeh; Henry Q. Xiong; Kenzo Iizuka; Howard S. Hochster; Scott Kopetz


Investigational New Drugs | 2018

Two phase I, pharmacokinetic, and pharmacodynamic studies of DFP-10917, a novel nucleoside analog with 14-day and 7-day continuous infusion schedules

Kamalesh Sankhala; Chris H. Takimoto; Alain C. Mita; Henry Xiong; Jordi Rodon; Amir Mehrvarz Sarshekeh; K. Burns; Kenzo Iizuka; Scott Kopetz


Annals of Oncology | 2016

O3-5-4Phase I study of DFP-11207, a novel chemotherapeutic agent, in patients with solid tumors by reasonable dose escalation

Jaffer A. Ajani; Cathy Eng; Milind Javle; Katrina Hernandez; Barry Douglas Anderson; Chun Zhang; Kenzo Iizuka

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Courtney D. DiNardo

University of Texas MD Anderson Cancer Center

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Elias Jabbour

University of Texas MD Anderson Cancer Center

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Gautam Borthakur

University of Texas MD Anderson Cancer Center

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Guillermo Garcia-Manero

University of Texas MD Anderson Cancer Center

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Hagop M. Kantarjian

University of Texas MD Anderson Cancer Center

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