The Experts below are selected from a list of 126 Experts worldwide ranked by ideXlab platform
Hiroshi Maeda - One of the best experts on this subject based on the ideXlab platform.
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Macromolecular Therapeutics
Clinical Pharmacokinetics, 2003Co-Authors: Khaled Greish, Jun Fang, Takao Inutsuka, Akinori Nagamitsu, Hiroshi MaedaAbstract:Macromolecular drugs (also referred to as polymeric drugs) are a diverse group of drugs including polymer-conjugated drugs, polymeric micelles, liposomal drugs and solid phase depot formulations of various agents. In this review we will consider only water-soluble macromolecular drugs. In common, such drugs have high molecular weights, more than 40 kDa, which enables them to overcome renal excretion. Consequently, this group of drugs can attain prolonged plasma or local half-lives. The prolonged circulating time of these macromolecules enables them to utilise the vascular abnormalities of solid tumour tissues, a phenomenon called the enhanced permeability and retention (EPR) effect. The EPR effect facilitates extravasation of polymeric drugs more selectively at tumour tissues, and this selective targeting to solid tumour tissues may lead to superior therapeutic benefits with fewer systemic adverse effects. This contrasts with conventional low-molecular-weight drugs, where intratumour concentration diminishes rapidly in parallel with plasma concentration. The EPR effect is also operative in inflammatory tissues, which justifies the development and use of this class of drugs in infectious and inflammatory conditions. At the present time, several polymeric drugs have been approved by regulatory agencies. These include Zinostatin stimalamer (copolymer styrene maleic acid-conjugated neocarZinostatin, or SMANCS) and polyethyleneglycol-conjugated interferon-α-2a. This article discusses these and other polymeric drugs in the setting of targeting to solid tumours.
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Macromolecular therapeutics: advantages and prospects with special emphasis on solid tumour targeting.
Clinical pharmacokinetics, 2003Co-Authors: Khaled Greish, Jun Fang, Takao Inutsuka, Akinori Nagamitsu, Hiroshi MaedaAbstract:Macromolecular drugs (also referred to as polymeric drugs) are a diverse group of drugs including polymer-conjugated drugs, polymeric micelles, liposomal drugs and solid phase depot formulations of various agents. In this review we will consider only water-soluble macromolecular drugs. In common, such drugs have high molecular weights, more than 40 kDa, which enables them to overcome renal excretion. Consequently, this group of drugs can attain prolonged plasma or local half-lives. The prolonged circulating time of these macromolecules enables them to utilise the vascular abnormalities of solid tumour tissues, a phenomenon called the enhanced permeability and retention (EPR) effect. The EPR effect facilitates extravasation of polymeric drugs more selectively at tumour tissues, and this selective targeting to solid tumour tissues may lead to superior therapeutic benefits with fewer systemic adverse effects. This contrasts with conventional low-molecular-weight drugs, where intratumour concentration diminishes rapidly in parallel with plasma concentration. The EPR effect is also operative in inflammatory tissues, which justifies the development and use of this class of drugs in infectious and inflammatory conditions. At the present time, several polymeric drugs have been approved by regulatory agencies. These include Zinostatin stimalamer (copolymer styrene maleic acid-conjugated neocarZinostatin, or SMANCS) and polyethyleneglycol-conjugated interferon-alpha-2a. This article discusses these and other polymeric drugs in the setting of targeting to solid tumours.
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Host-Mediated Antitumor Activity Induced by NeocarZinostatin and Its Polymer-Conjugated Derivative SMANCS in Tumor-Bearing Mice
Neocarzinostatin, 1997Co-Authors: Etsuko Masuda, Hiroshi MaedaAbstract:Pretreatment with neocarZinostatin (NCS) or its polymer-conjugated derivative, Zinostatin stimalamer (usually called SMANCS), induced Meth A tumor eradication in Balb/c mice. Tumor eradication was induced by a single administration of NCS or SMANCS between 4 weeks and 1 day before tumor transplantation. Meth A was always eradicated after transient growth. These results suggested that Meth A was eradicated by host-mediated antitumor activity induced by NCS or SMANCS. Pretreatment with these drugs also suppressed the growth of Colon 26 carcinoma and Sarcoma 180. Apo-SMANCS, which lacks cytocidal activity, did not induce antitumor activity, suggesting that cytocidal activity was required for induction of host-mediated antitumor activity. Spleen cells from Meth A-bearing mice pretreated with NCS or SMANCS showed tumor-neutralizing activity, and the effector cells were T cells, but the spleen cells did not exhibit cytotoxic activity or cytotoxic T-lymphocyte (CTL) activity. Flow cytometric analysis indicated that a decrease of B cells was prominent in spleen cells and lymph node cells after NCS or SMANCS treatment. In vivo depletion experiments using antibodies and carrageenan suggested that the effector cells for tumor eradication were asialo-GM1+/Lyt2+/Thy1.2+ and possibly asialo GM1−/Lyt2+/Thy1.2+, and that asialo GM1−/Lyt2+/Thy1.2+ cells were essential for the generation of antitumor activity. It was also suggested that host-mediated antitumor activity was augmented not only by pretreatment but also by posttreatment. These studies suggest that NCS or SMANCS exhibits antitumor activity through both direct cytotoxicity and indirect host-mediated antitumor activity.
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Changes in cellular components of spleen and lymph node cells and the effector cells responsible for Meth A tumor eradication induced by Zinostatin stimalamer.
Cancer research, 1996Co-Authors: Etsuko Masuda, Hiroshi MaedaAbstract:Abstract We reported previously that pretreatment with Zinostatin stimalamer (ZSS) eradicated Meth A tumors in BALB/c mice. We herein investigated cellular components of spleen and lymph node cells of Meth A-bearing ZSS-pretreated mice by flow cytometry; the antitumor effector cells by in vivo depletion of T cells, NK cells, or macrophages; and host-mediated antitumor activity associated with ZSS treatment after tumor transplantation. ZSS given on day -3 transiently decreased the number of spleen cells. The percentage of T cells increased, but B cells and macrophages decreased. B cells decreased in inguinal lymph nodes in Meth A-bearing ZSS-pretreated mice, but increased in Meth A-bearing control mice. In vivo depletion experiments using antibodies or carrageenan showed that antitumor effector cells for tumor eradication are Thy1.2+/Lyt2.2+ and that at least a part of them are asialo GM1+. Thy1.2+/Lyt2.2+/asialo GM1- cells are important in generation of the antitumor activity of ZSS; however, L3T4+ T cells are also involved in initiation of tumor eradication. The result of ZSS treatment after tumor transplantation suggests that ZSS might exhibit antitumor activity by augmentating host-mediated antitumor resistance, as well as its intrinsic cytocidal activity.
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Antitumor resistance induced by Zinostatin stimalamer (ZSS), a polymer-conjugated neocarZinostatin (NCS) derivative
Cancer Immunology Immunotherapy, 1995Co-Authors: Etsuko Masuda, Hiroshi MaedaAbstract:Zinostatin stimalamer (ZSS) is a new anticancer agent derived from neocarZinostatin (NCS), which is synthesized by conjugation of one molecule of NCS and two molecules of poly(styrene-co-maleic acid). ZSS exhibited potent in vitro and in vivo antitumor activity in preclinical experiments, and a clinical trial of the intra-arterial administration of ZSS with iodized oil on hepatocellular carcinoma showed potent antitumor activity. We investigated the effect of ZSS and NCS on antitumor resistance and found that pretreatment with either drug suppressed the growth of MethA tumors in Balb/c mice and induced tumor eradication when given separately by single administration at therapeutic doses between 1 day and 4 weeks before tumor transplantation. The findings that the cytocidal activity of these drugs was not detected in vivo at the time of tumor transplantation and that tumor regression was preceded by a period of transient growth suggested that tumor regression was due to host-mediated antitumor activity induced by these drugs. Pretreatment with ZSS or NCS also suppressed the growth of Colon 26 carcinoma and Sarcoma 180. The finding that NCS showed the same effect as ZSS suggests that poly(styrene-comaleic acid) is not essential for the induction of hostmediated antitumor activity. Furthermore, apo-ZSS, which lacks cytocidal activity, did not induce antitumor activity. From this, it is suggested that the cytocidal effect of ZSS involves the induction of hostmediated antitumor resistance. In athymic Balb/c nu/nu mice, pretreatment with ZSS or NCS did not induce tumor eradication, suggesting that mature T lymphocytes play an important role in tumor eradication. Challenging MethA was rejected withot transient growth in mice that had been cured of MethA, but challenging Colon 26 was not, showing that anti-MethA resistance was augmented selectively in the MethaA-eradicated mice. Splenocytes from MethA-bearing mice pretreated with the drug showed tumorneutralizing activity beginning 14 days after tumor transplantation. Tumor-neutralizing activity was only induced after MethA transplantation. The effector cells of this tumor-neutralizing activity were Thy1.2^+ T lymphocytes that had been passed through a nylonwool column, but no significant augmentation of cell-mediated cytotoxic activity of splenocytes from MethA-eradicated mice was observed in vitro.
Takuji Okusaka - One of the best experts on this subject based on the ideXlab platform.
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A randomized phase II trial of intra-arterial chemotherapy using SM-11355 (Miriplatin) for hepatocellular carcinoma
Investigational New Drugs, 2012Co-Authors: Takuji Okusaka, Hiroshi Ishii, Hiroshi Kasugai, Masatoshi Kudo, Michio Sata, Katsuaki Tanaka, Yasukazu Shioyama, Kazuaki Chayama, Hiromitsu Kumada, Masaharu YoshikawaAbstract:Background SM-11355 is a platinum complex developed to treat hepatocellular carcinoma (HCC) via administration into the hepatic artery as a sustained-release suspension in iodized oil. We conducted a multicenter phase II trial in patients with HCC to evaluate the efficacy and safety of SM-11355, using a Zinostatin stimalamer suspension in iodized oil as a reference. Methods Patients with unresectable HCC were randomized 2:1 to receive administration of the SM-11355 or Zinostatin stimalamer suspension into the hepatic artery. A second injection was given 4–12 weeks later. Efficacy was evaluated by CT 3 months after treatment and categorized as therapeutic effect (TE) V to I, where TE V was defined as disappearance or 100% necrosis of all treated tumors. Results A total of 122 patients were evaluated for efficacy and toxicity (SM-11355, n = 83; Zinostatin stimalamer, n = 39). Baseline characteristics were similar in the two groups. The TE V rates were 26.5% (22/83) and 17.9% (7/39) in the SM-11355 and Zinostatin stimalamer groups, respectively. In the SM-11355 group,the most frequent drug-related adverse events (AEs) of ≥ grade 3 were elevated AST, elevated ALT, thrombocytopenia, and hyperbilirubinemia. The AEs with the largest difference between the two groups (SM-11355 vs. Zinostatin stimalamer) were hepatic vascular injury (0 vs. 48.4%) and eosinophilia (84.3 vs. 41.0%). The 2-year and 3-year survival rates were 75.9% vs. 70.3% and 58.4% vs. 48.7%, respectively. Conclusions The results suggest that SM-11355 in iodized oil has similar efficacy to Zinostatin stimalamer and that repeated dosing of SM-11355 is possible without hepatic vascular injury in cases of relapse.
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Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: A randomized phase III trial
Journal of hepatology, 2009Co-Authors: Takuji Okusaka, Hiroshi Kasugai, Masatoshi Kudo, Michio Sata, Katsuaki Tanaka, Yasukazu Shioyama, Hiromitsu Saisho, Yukio Osaki, Shigetoshi Fujiyama, Takashi KumadaAbstract:Background/Aims Transcatheter arterial chemoembolization (TACE) is a combination of transarterial infusion chemotherapy (TAI) and embolization, and has been widely used to treat patients with hepatocellular carcinoma (HCC). However, since the impact of adding embolization on the survival of patients treated with TAI had never been evaluated in a phase III study, we conducted a multi-center, open-label trial comparing TACE and TAI to assess the effect of adding embolization on survival. Methods Patients with newly diagnosed unresectable HCC were randomly assigned to either a TACE group or a TAI group. Zinostatin stimalamer was injected into the hepatic artery, together with gelatin sponge in the TACE group and without gelatin sponge in the TAI group. Treatment was repeated when follow-up computed tomography showed the appearance of new lesions in the liver or re-growth of previously treated tumors. Results Seventy-nine patients were assigned to the TACE group, and 82 were assigned to the TAI group. The two groups were comparable with respect to their baseline characteristics. At the time of the analysis, 51 patients in the TACE group and 58 in the TAI group had died. The median overall survival time was 646days in the TACE group and 679days in the TAI group ( p =0.383). Conclusions The results of this study suggest that treatment intensification by adding embolization did not increase survival over TAI with Zinostatin stimalamer alone in patients with HCC.
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A randomized phase II trial of intra-arterial chemotherapy using a novel lipophilic platinum derivative (SM-11355) in comparison with Zinostatin stimalamer in patients with hepatocellular carcinoma
Journal of Clinical Oncology, 2009Co-Authors: Takuji Okusaka, Hiroshi Kasugai, Hiroshi IshiiAbstract:4583 Background: SM-11355 (Miriplatin Hydrate) is a platinum complex developed to treat HCC via administration into the hepatic artery as a sustained-release formulation suspended in lipiodol. We c...
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Transcatheter arterial embolization with Zinostatin stimalamer for hepatocellular carcinoma.
Oncology, 2002Co-Authors: Takuji Okusaka, Shuichi Okada, Hideki Ueno, Masafumi Ikeda, Ryoko Iwata, Hiroyoshi Furukawa, Kenichi Takayasu, Noriyuki Moriyama, Tosiya Sato, Keiko SatoAbstract:Zinostatin stimalamer (SMANCS) is a lipophilic intra-arterial chemotherapeutic agent for hepatocellular carcinoma (HCC). In our previous study, transcatheter arterial infusion chemotherapy using SMANC
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Targeted transarterial oily chemoembolization for small foci of hepatocellular carcinoma using a unified helical CT and angiography system: analysis of factors affecting local recurrence and survival rates.
AJR. American journal of roentgenology, 2001Co-Authors: Kenichi Takayasu, Takuji Okusaka, Shuichi Okada, Ryoko Iwata, Hiroyoshi Furukawa, Noriyuki Moriyama, Yoshihisa Muramatsu, Tetsuo Maeda, Yukio Muramatsu, Hideki UenoAbstract:OBJECTIVE. We assessed the local recurrence rate after a single targeted transarterial oily chemoembolization for small hepatocellular carcinoma with the unified helical CT and angiography system and analyzed the factors affecting the local recurrence rate and survival rate with Cox proportional hazards model.MATERIALS AND METHODS. For 54 consecutive patients with 71 small hepatocellular carcinomas (≤5 cm) with no more than two associated lesions, targeted oily chemoembolization was performed with an emulsion of doxorubicin hydrochloride mixed with iodized oil or a suspension of Zinostatin stimalamer followed by gelatin sponge particles. When local recurrence or a new lesion appeared, follow-up targeted oily chemoembolization was performed.RESULTS. For 52 of 71 lesions, the catheterization to a subsegmental or more distal feeding artery could be performed. Local recurrence was recognized in 33.2% at 1 year and 37.8% at 2 and 3 years. The significant factors that affected local recurrence were tumor size (...
Etsuko Masuda - One of the best experts on this subject based on the ideXlab platform.
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Host-Mediated Antitumor Activity Induced by NeocarZinostatin and Its Polymer-Conjugated Derivative SMANCS in Tumor-Bearing Mice
Neocarzinostatin, 1997Co-Authors: Etsuko Masuda, Hiroshi MaedaAbstract:Pretreatment with neocarZinostatin (NCS) or its polymer-conjugated derivative, Zinostatin stimalamer (usually called SMANCS), induced Meth A tumor eradication in Balb/c mice. Tumor eradication was induced by a single administration of NCS or SMANCS between 4 weeks and 1 day before tumor transplantation. Meth A was always eradicated after transient growth. These results suggested that Meth A was eradicated by host-mediated antitumor activity induced by NCS or SMANCS. Pretreatment with these drugs also suppressed the growth of Colon 26 carcinoma and Sarcoma 180. Apo-SMANCS, which lacks cytocidal activity, did not induce antitumor activity, suggesting that cytocidal activity was required for induction of host-mediated antitumor activity. Spleen cells from Meth A-bearing mice pretreated with NCS or SMANCS showed tumor-neutralizing activity, and the effector cells were T cells, but the spleen cells did not exhibit cytotoxic activity or cytotoxic T-lymphocyte (CTL) activity. Flow cytometric analysis indicated that a decrease of B cells was prominent in spleen cells and lymph node cells after NCS or SMANCS treatment. In vivo depletion experiments using antibodies and carrageenan suggested that the effector cells for tumor eradication were asialo-GM1+/Lyt2+/Thy1.2+ and possibly asialo GM1−/Lyt2+/Thy1.2+, and that asialo GM1−/Lyt2+/Thy1.2+ cells were essential for the generation of antitumor activity. It was also suggested that host-mediated antitumor activity was augmented not only by pretreatment but also by posttreatment. These studies suggest that NCS or SMANCS exhibits antitumor activity through both direct cytotoxicity and indirect host-mediated antitumor activity.
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Changes in cellular components of spleen and lymph node cells and the effector cells responsible for Meth A tumor eradication induced by Zinostatin stimalamer.
Cancer research, 1996Co-Authors: Etsuko Masuda, Hiroshi MaedaAbstract:Abstract We reported previously that pretreatment with Zinostatin stimalamer (ZSS) eradicated Meth A tumors in BALB/c mice. We herein investigated cellular components of spleen and lymph node cells of Meth A-bearing ZSS-pretreated mice by flow cytometry; the antitumor effector cells by in vivo depletion of T cells, NK cells, or macrophages; and host-mediated antitumor activity associated with ZSS treatment after tumor transplantation. ZSS given on day -3 transiently decreased the number of spleen cells. The percentage of T cells increased, but B cells and macrophages decreased. B cells decreased in inguinal lymph nodes in Meth A-bearing ZSS-pretreated mice, but increased in Meth A-bearing control mice. In vivo depletion experiments using antibodies or carrageenan showed that antitumor effector cells for tumor eradication are Thy1.2+/Lyt2.2+ and that at least a part of them are asialo GM1+. Thy1.2+/Lyt2.2+/asialo GM1- cells are important in generation of the antitumor activity of ZSS; however, L3T4+ T cells are also involved in initiation of tumor eradication. The result of ZSS treatment after tumor transplantation suggests that ZSS might exhibit antitumor activity by augmentating host-mediated antitumor resistance, as well as its intrinsic cytocidal activity.
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Antitumor resistance induced by Zinostatin stimalamer (ZSS), a polymer-conjugated neocarZinostatin (NCS) derivative
Cancer Immunology Immunotherapy, 1995Co-Authors: Etsuko Masuda, Hiroshi MaedaAbstract:Zinostatin stimalamer (ZSS) is a new anticancer agent derived from neocarZinostatin (NCS), which is synthesized by conjugation of one molecule of NCS and two molecules of poly(styrene-co-maleic acid). ZSS exhibited potent in vitro and in vivo antitumor activity in preclinical experiments, and a clinical trial of the intra-arterial administration of ZSS with iodized oil on hepatocellular carcinoma showed potent antitumor activity. We investigated the effect of ZSS and NCS on antitumor resistance and found that pretreatment with either drug suppressed the growth of MethA tumors in Balb/c mice and induced tumor eradication when given separately by single administration at therapeutic doses between 1 day and 4 weeks before tumor transplantation. The findings that the cytocidal activity of these drugs was not detected in vivo at the time of tumor transplantation and that tumor regression was preceded by a period of transient growth suggested that tumor regression was due to host-mediated antitumor activity induced by these drugs. Pretreatment with ZSS or NCS also suppressed the growth of Colon 26 carcinoma and Sarcoma 180. The finding that NCS showed the same effect as ZSS suggests that poly(styrene-comaleic acid) is not essential for the induction of hostmediated antitumor activity. Furthermore, apo-ZSS, which lacks cytocidal activity, did not induce antitumor activity. From this, it is suggested that the cytocidal effect of ZSS involves the induction of hostmediated antitumor resistance. In athymic Balb/c nu/nu mice, pretreatment with ZSS or NCS did not induce tumor eradication, suggesting that mature T lymphocytes play an important role in tumor eradication. Challenging MethA was rejected withot transient growth in mice that had been cured of MethA, but challenging Colon 26 was not, showing that anti-MethA resistance was augmented selectively in the MethaA-eradicated mice. Splenocytes from MethA-bearing mice pretreated with the drug showed tumorneutralizing activity beginning 14 days after tumor transplantation. Tumor-neutralizing activity was only induced after MethA transplantation. The effector cells of this tumor-neutralizing activity were Thy1.2^+ T lymphocytes that had been passed through a nylonwool column, but no significant augmentation of cell-mediated cytotoxic activity of splenocytes from MethA-eradicated mice was observed in vitro.
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Antitumor resistance induced by Zinostatin stimalamer (ZSS), a polymer-conjugated neocarZinostatin (NCS) derivative. I. Meth A tumor eradication and tumor-neutralizing activity in mice pretreated with ZSS or NCS.
Cancer immunology immunotherapy : CII, 1995Co-Authors: Etsuko Masuda, Hiroshi MaedaAbstract:Zinostatin stimalamer (ZSS) is a new anticancer agent derived from neocarZinostatin (NCS), which is synthesized by conjugation of one molecule of NCS and two molecules of poly(styrene-co-maleic acid). ZSS exhibited potent in vitro and in vivo antitumor activity in preclinical experiments, and a clinical trial of the intra-arterial administration of ZSS with iodized oil on hepatocellular carcinoma showed potent antitumor activity. We investigated the effect of ZSS and NCS on antitumor resistance and found that pretreatment with either drug suppressed the growth of MethA tumors in Balb/c mice and induced tumor eradication when given separately by single administration at therapeutic doses between 1 day and 4 weeks before tumor transplantation. The findings that the cytocidal activity of these drugs was not detected in vivo at the time of tumor transplantation and that tumor regression was preceded by a period of transient growth suggested that tumor regression was due to host-mediated antitumor activity induced by these drugs. Pretreatment with ZSS or NCS also suppressed the growth of Colon 26 carcinoma and Sarcoma 180. The finding that NCS showed the same effect as ZSS suggests that poly(styrene-comaleic acid) is not essential for the induction of hostmediated antitumor activity. Furthermore, apo-ZSS, which lacks cytocidal activity, did not induce antitumor activity. From this, it is suggested that the cytocidal effect of ZSS involves the induction of hostmediated antitumor resistance. In athymic Balb/cnu/nu mice, pretreatment with ZSS or NCS did not induce tumor eradication, suggesting that mature T lymphocytes play an important role in tumor eradication. Challenging MethA was rejected withot transient growth in mice that had been cured of MethA, but challenging Colon 26 was not, showing that anti-MethA resistance was augmented selectively in the MethaA-eradicated mice. Splenocytes from MethA-bearing mice pretreated with the drug showed tumorneutralizing activity beginning 14 days after tumor transplantation. Tumor-neutralizing activity was only induced after MethA transplantation. The effector cells of this tumor-neutralizing activity were Thy1.2+ T lymphocytes that had been passed through a nylonwool column, but no significant augmentation of cell-mediated cytotoxic activity of splenocytes from MethA-eradicated mice was observed in vitro.
Hiroshi Ishii - One of the best experts on this subject based on the ideXlab platform.
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A randomized phase II trial of intra-arterial chemotherapy using SM-11355 (Miriplatin) for hepatocellular carcinoma
Investigational New Drugs, 2012Co-Authors: Takuji Okusaka, Hiroshi Ishii, Hiroshi Kasugai, Masatoshi Kudo, Michio Sata, Katsuaki Tanaka, Yasukazu Shioyama, Kazuaki Chayama, Hiromitsu Kumada, Masaharu YoshikawaAbstract:Background SM-11355 is a platinum complex developed to treat hepatocellular carcinoma (HCC) via administration into the hepatic artery as a sustained-release suspension in iodized oil. We conducted a multicenter phase II trial in patients with HCC to evaluate the efficacy and safety of SM-11355, using a Zinostatin stimalamer suspension in iodized oil as a reference. Methods Patients with unresectable HCC were randomized 2:1 to receive administration of the SM-11355 or Zinostatin stimalamer suspension into the hepatic artery. A second injection was given 4–12 weeks later. Efficacy was evaluated by CT 3 months after treatment and categorized as therapeutic effect (TE) V to I, where TE V was defined as disappearance or 100% necrosis of all treated tumors. Results A total of 122 patients were evaluated for efficacy and toxicity (SM-11355, n = 83; Zinostatin stimalamer, n = 39). Baseline characteristics were similar in the two groups. The TE V rates were 26.5% (22/83) and 17.9% (7/39) in the SM-11355 and Zinostatin stimalamer groups, respectively. In the SM-11355 group,the most frequent drug-related adverse events (AEs) of ≥ grade 3 were elevated AST, elevated ALT, thrombocytopenia, and hyperbilirubinemia. The AEs with the largest difference between the two groups (SM-11355 vs. Zinostatin stimalamer) were hepatic vascular injury (0 vs. 48.4%) and eosinophilia (84.3 vs. 41.0%). The 2-year and 3-year survival rates were 75.9% vs. 70.3% and 58.4% vs. 48.7%, respectively. Conclusions The results suggest that SM-11355 in iodized oil has similar efficacy to Zinostatin stimalamer and that repeated dosing of SM-11355 is possible without hepatic vascular injury in cases of relapse.
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A randomized phase II trial of intra-arterial chemotherapy using a novel lipophilic platinum derivative (SM-11355) in comparison with Zinostatin stimalamer in patients with hepatocellular carcinoma
Journal of Clinical Oncology, 2009Co-Authors: Takuji Okusaka, Hiroshi Kasugai, Hiroshi IshiiAbstract:4583 Background: SM-11355 (Miriplatin Hydrate) is a platinum complex developed to treat HCC via administration into the hepatic artery as a sustained-release formulation suspended in lipiodol. We c...
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A Phase I Study of Hepatic Arterial Infusion Chemotherapy with Zinostatin Stimalamer Alone for Hepatocellular Carcinoma
Japanese Journal of Clinical Oncology, 2003Co-Authors: Hiroshi Ishii, Junji Furuse, Yasushi Maru, Masahiro Yoshino, Michitaka Nagase, Takayuki HayashiAbstract:Background: Hepatic arterial infusion of Zinostatin stimalamer and lipiodol emulsion shows a moderate activity against hepatocellular carcinoma. However, the anti-tumor activity of Zinostatin stimalamer alone is uncertain. Methods: The primary endpoint was to evaluate the frequency of dose-limiting toxicity and determine the maximum-tolerated dose of Zinostatin stimalamer when used by intra-arterial infusion. The candidates for this study were patients with hepatocellular carcinoma no longer amenable to established forms of treatment. Hepatic arterial infusion chemotherapy was performed by selectively introducing a catheter into the hepatic artery with Zinostatin stimalamer alone. Treatment was repeated at 4–8-week intervals until disease progression or the appearance of unacceptable toxicity. The starting dose of Zinostatin stimalamer was 3 mg/m 2 , and doses were increased in 1 mg/m 2 increments in successive cohorts. At least three patients were treated at each dose level and three additional patients were treated in the presence of dose-limiting toxicity. Results: Twelve patients were entered into this trial. Dose-limiting toxicity was observed in one of six patients at 3 mg/m 2 , and in two of six patients at 4 mg/m 2 . The maximum-tolerated dose was judged to be 3 mg/m 2 with liver dysfunction and serum creatinine increase as the doselimiting toxicity. There was one early death suggested to be related to the protocol treatment. None of the 12 patients achieved an objective tumor response. Conclusion: Hepatic arterial infusion with a Zinostatin stimalamer of 3 mg/m 2 may be tolerated, but not active, in patients with far advanced hepatocellular carcinoma.
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Transarterial chemotherapy with Zinostatin stimalamer for hepatocellular carcinoma
Oncology, 1998Co-Authors: Takuji Okusaka, Hiroshi Ishii, Shuichi Okada, Masafumi Ikeda, Ryoko Iwata, Hiroyoshi Furukawa, Kenichi Takayasu, Hidekazu Nakasuka, Hiroyasu Nagahama, Yukihiro NakanishiAbstract:Zinostatin stimalamer (SMANCS) is a lipophilic intra-arterial chemotherapeutic agent for hepatocellular carcinoma (HCC). Thirty HCC patients underwent transcatheter arterial injection of 4 mg SMANCS-lipiodol emulsion. Their responses were evaluated by computed tomography 1 month after treatment. Complete response (CR) was defined as disappearance or 100% necrosis of all tumors. Partial response (PR) was defined as > or = 50% reduction and/or > or = 50% necrosis. We regarded the lipiodol accumulation in tumors as being necrotic. CR and PR were observed in 8 patients (27%) and 4 patients (13%), respectively, and the overall response rate (CR + PR/all patients) was 40% (12/30). Of 12 patients whose serum alpha-fetoprotein levels had been more than 200 ng/ml before treatment, 5 patients (42%) showed more than 50% reduction in this level within 1 month after treatment. Toxicity was quite acceptable, although grade 4 toxicity (WHO) was observed as liver dysfunction in 1 patient. Transarterial chemotherapy with SMANCS, which is well tolerated, appears to have moderate antitumor effect in patients with HCC.
Kazuaki Chayama - One of the best experts on this subject based on the ideXlab platform.
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A randomized phase II trial of intra-arterial chemotherapy using SM-11355 (Miriplatin) for hepatocellular carcinoma
Investigational New Drugs, 2012Co-Authors: Takuji Okusaka, Hiroshi Ishii, Hiroshi Kasugai, Masatoshi Kudo, Michio Sata, Katsuaki Tanaka, Yasukazu Shioyama, Kazuaki Chayama, Hiromitsu Kumada, Masaharu YoshikawaAbstract:Background SM-11355 is a platinum complex developed to treat hepatocellular carcinoma (HCC) via administration into the hepatic artery as a sustained-release suspension in iodized oil. We conducted a multicenter phase II trial in patients with HCC to evaluate the efficacy and safety of SM-11355, using a Zinostatin stimalamer suspension in iodized oil as a reference. Methods Patients with unresectable HCC were randomized 2:1 to receive administration of the SM-11355 or Zinostatin stimalamer suspension into the hepatic artery. A second injection was given 4–12 weeks later. Efficacy was evaluated by CT 3 months after treatment and categorized as therapeutic effect (TE) V to I, where TE V was defined as disappearance or 100% necrosis of all treated tumors. Results A total of 122 patients were evaluated for efficacy and toxicity (SM-11355, n = 83; Zinostatin stimalamer, n = 39). Baseline characteristics were similar in the two groups. The TE V rates were 26.5% (22/83) and 17.9% (7/39) in the SM-11355 and Zinostatin stimalamer groups, respectively. In the SM-11355 group,the most frequent drug-related adverse events (AEs) of ≥ grade 3 were elevated AST, elevated ALT, thrombocytopenia, and hyperbilirubinemia. The AEs with the largest difference between the two groups (SM-11355 vs. Zinostatin stimalamer) were hepatic vascular injury (0 vs. 48.4%) and eosinophilia (84.3 vs. 41.0%). The 2-year and 3-year survival rates were 75.9% vs. 70.3% and 58.4% vs. 48.7%, respectively. Conclusions The results suggest that SM-11355 in iodized oil has similar efficacy to Zinostatin stimalamer and that repeated dosing of SM-11355 is possible without hepatic vascular injury in cases of relapse.
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Effect of arterial administration of a high-molecular weight antitumor agent, styrene maleic acid neocarZinostatin, in embolization-resistant liver cancer
International Journal of Clinical Oncology, 1999Co-Authors: K. Ikeda, Kazuaki Chayama, Satoshi Saitoh, Yoshiyuki Suzuki, Akihito Tsubota, Masahiro Kobayashi, Isao Koida, Mizuho Kobayashi, Yasuji Arase, Naoya MurashimaAbstract:Background. Hepatocellular carcinoma often shows a resistance to transcatheter arterial embolization in the course of therapy repetition. Methods. Forty-four of 103 consecutive patients with hepatocellular carcinoma showing a resistance to repeated embolization therapy were treated with intra-arterial injection of the high-molecular weight antitumor agent styrene-maleic acid neocarZinostatin (Zinostatin) mixed with Lipiodol (group A). The remaining 59 patients received repeated embolization with epirubicin given in the same way (group B). Results. In group A, computerized tomography scans 3 months after the therapy showed "complete" accumulation of Lipiodol in 2 patients (4.5%), and "good" accumulation (50%–99%) in 11 (25.0%); 10%–49% accumulation was shown in 12 patients (41.9%), and less than 10% in 19 patients (32.6%). In group B, 1 patient (1.7%) showed complete accumulation, 4 (6.8%) showed "good" accumulation, 10 (16.9%) showed 10%–49% accumulation, and 44 (74.6%) showed less than 10%. Multivariate logistic regression analysis showed that factors affecting Lipiodol accumulation after therapy included tumor multiplicity ( P < 0.0001), use of Zinostatin ( P = 0.010), and decompensation of cirrhosis ( P = 0.049). In the 44 patients with Zinostatin injection, tumor size was the only factor affecting Lipiodol accumulation. Survival rates in groups A and B were 70.4% and 45.8%, respectively, at the end of the first year, 36.8% and 17.3% at the end of the second year, and 24.5% and 13.0% at the end of the third year ( P = 0.0087). Conclusion. Intra-arterial Zinostatin injection therapy increased the Lipiodol accumulation rate and the survival rate in patients with embolization-resistant HCC, and the best candidates for the treatment were patients with smaller liver cancer of 50 mm.
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Effect of arterial administration of a high molecular weight anti-tumor agent, styrene maleic acid neocarZinostatin, for multiple small liver cancer—A pilot study
Journal of Gastroenterology, 1997Co-Authors: K. Ikeda, Kazuaki Chayama, Satoshi Saitoh, Yoshiyuki Suzuki, Akihito Tsubota, Masahiro Kobayashi, Isao Koida, Yasuji Arase, Naoya Murashima, Hiromitsu KumadaAbstract:To assess the efficacy of the Zinostatin derivative, the anti-tumor agent, styrene-maleic acid neocarZinostatin, in treating multiple small liver cancers, 29 patients with multiple hepatocellular carcinoma of 3 cm or less in diameter were treated with intraarterial injections of this high molecular weight agent, mixed with Lipiodol. Computed tomography 3 months after the first therapy showed complete deposition of Lipiodol in the entire area of the original tumor in 8 patients (27.6%), 50%–99% deposition in 4 (13.8%), 10%–49% in 10 (34.5%), and less than 10% in 7 (24.1%). After repeated injections, Lipiodol deposition in the entire area of the original tumor was found in 11 patients (37.9%). The degree of Lipiodol deposition depended on the angiographic vascularity of the tumor and on the images of the computed tomogram during arterial protography. Although complete deposition of Lipiodol was found in all tumors in 10 (58.8%) of the 17 patients with well demarcated round hypervascularity, only 1 (8.3%) of 12 patients with ill demarcated tumors showed complete deposition of Lipiodol in the tumors. Taking into account that hypervascularity on angiograms was closely correlated with the degree of Lipiodol accumulation on computed tomograms taken later, it appears that well demarcated round-shaped liver cancer is the best candidate for styrene-maleic acid neocarZinostatin therapy.
