Antitumor Effect of NK012, a 7-Ethyl-10-Hydroxycamptothecin–Incorporating Polymeric Micelle, on U87MG Orthotopic Glioblastoma in Mice Compared with Irinotecan Hydrochloride in Combination with Bevacizumab

Kuroda, Jun; Kuratsu, Jun Ichi; Yasunaga, Masahiro; Koga, Yoshikatsu; Kenmotsu, Hirotsugu; Sugino, Takashi; Matsumura, Yasuhiro

doi:10.1158/1078-0432.ccr-09-2393

Cited by 35 publications

(22 citation statements)

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“…To our knowledge, this is the first study to show that NK012 completely eradicated orthotopic tumors in an orthotopic model, in addition to our previously reported potent antitumor effects of NK012 against various models using human cancer cell lines (17)(18)(19)(20)25). The strong antitumor activity of NK012 is attributable to the high concentration of free SN-38 released from NK012 in the tumor, which is higher than any other concentrations previously reported.…”

Section: Discussionmentioning

confidence: 50%

Detailed Distribution of NK012, an SN-38–Incorporating Micelle, in the Liver and Its Potent Antitumor Effects in Mice Bearing Liver Metastases

Takahashi

Ohkohchi

Yasunaga

et al. 2010

Clinical Cancer Research

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Purpose: To clarify and compare the antitumor effects and specific biodistribution of NK012, an SN-38-incorporating polymeric micelle, in mice bearing multiple liver metastases of human colon cancer HT-29 cells with irinotecan hydrochloride (CPT-11).Experimental Design: The maximum tolerable dose of NK012 (30 mg/kg) or CPT-11 (66.7 mg/kg) was i.v. administered three times every 4 days to mice bearing metastases to the liver colonized 7 days after the portal administration of HT-29 cells (n = 6). In vivo antitumor effects were evaluated by bioluminescence imaging and histopathologic examination. Drug biodistribution was analyzed by high-performance liquid chromatography and fluorescence microscopy (n = 3).Results: NK012 eradicated the liver metastases and produced a significant longer survival rate than CPT-11 (P = 0.0006). High-performance liquid chromatography showed the prolonged distribution of NK012 and free SN-38 released from NK012 in the tumors, liver, and spleen for weeks after NK012 administration. On the other hand, the accumulation levels of CPT-11 and free SN-38 converted from CPT-11 rapidly decreased within 1 day after CPT-11 administration. In the liver metastases, fluorescence microscopy and immunohistochemistry showed that administered NK012 was distributed mainly adjacent to tumor vessels after 1 day. As for the normal liver, NK012 was distributed in Kupffer cells instead of hepatocytes for at least 7 days after administration.Conclusion: This study suggests that NK012 is strongly effective against liver metastases and does not damage the liver despite the long retention time of NK012 in Kupffer cells.

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Section: Discussionmentioning

confidence: 50%

Detailed Distribution of NK012, an SN-38–Incorporating Micelle, in the Liver and Its Potent Antitumor Effects in Mice Bearing Liver Metastases

Takahashi

Ohkohchi

Yasunaga

et al. 2010

Clinical Cancer Research

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“…Although other studies have demonstrated anti-cancer activity of CPT-11 in GBM murine models [18], [19], we did not perform a survival analysis in this study and further studies are thus needed to explore if the changes in the 18 F-FET uptake reflect true anti-cancer activity. The controversial topic about protein expression and mRNA level is another possible explanation for the observed unchanged Ki67 gene expression level in the present study.…”

Section: Discussionmentioning

confidence: 95%

“…(control). Anti-cancer activity of CPT-11 in orthotopic glioma xenografts has been reported previously and the treatment regimen was based on these studies [18], [19]. At tumor take the treatment response was monitored by MicroPET/CT for two weeks and treatments were given the day after the scans were performed.…”

Section: Methodsmentioning

confidence: 99%

The Use of Longitudinal 18F-FET MicroPET Imaging to Evaluate Response to Irinotecan in Orthotopic Human Glioblastoma Multiforme Xenografts

et al. 2014

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ObjectivesBrain tumor imaging is challenging. Although 18F-FET PET is widely used in the clinic, the value of 18F-FET MicroPET to evaluate brain tumors in xenograft has not been assessed to date. The aim of this study therefore was to evaluate the performance of in vivo 18F-FET MicroPET in detecting a treatment response in xenografts. In addition, the correlations between the 18F-FET tumor accumulation and the gene expression of Ki67 and the amino acid transporters LAT1 and LAT2 were investigated. Furthermore, Ki67, LAT1 and LAT2 gene expression in xenograft and archival patient tumors was compared.MethodsHuman GBM cells were injected orthotopically in nude mice and 18F-FET uptake was followed by weekly MicroPET/CT. When tumor take was observed, mice were treated with CPT-11 or saline weekly. After two weeks of treatment the brain tumors were isolated and quantitative polymerase chain reaction were performed on the xenograft tumors and in parallel on archival patient tumor specimens.ResultsThe relative tumor-to-brain (T/B) ratio of SUVmax was significantly lower after one week (123±6%, n = 7 vs. 147±6%, n = 7; p = 0.018) and after two weeks (142±8%, n = 5 vs. 204±27%, n = 4; p = 0.047) in the CPT-11 group compared with the control group. Strong negative correlations between SUVmax T/B ratio and LAT1 (r = −0.62, p = 0.04) and LAT2 (r = −0.67, p = 0.02) were observed. In addition, a strong positive correlation between LAT1 and Ki67 was detected in xenografts. Furthermore, a 1.6 fold higher expression of LAT1 and a 23 fold higher expression of LAT2 were observed in patient specimens compared to xenografts.Conclusions 18F-FET MicroPET can be used to detect a treatment response to CPT-11 in GBM xenografts. The strong negative correlation between SUVmax T/B ratio and LAT1/LAT2 indicates an export transport function. We suggest that 18F-FET PET may be used for detection of early treatment response in patients.

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“…Bevacizumab failure is also associated with increased expression and activity of the CXCR4/SDSF1α pathway [35]. To verify if in vivo administration of bevacizumab or sunitinib increased CXCR4/SDSF1α signaling, we treated female nude mice-bearing U87MG, U251, and T98G subcutaneous xenografts with bevacizumab (4 mg/kg iv every 4 days [36]) or sunitinib (40 mg/kg po qd, [37]). After 35 days of treatments, animals were sacrificed and tumor harvested.…”

Section: Resultsmentioning

confidence: 99%

The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma

et al. 2017

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BackgroundGlioblastoma recurrence after treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. It has been demonstrated that anti-VEGF/VEGFR therapies control the invasive phenotype and that relapse occurs through the increased activity of CXCR4. We therefore hypothesized that combining bevacizumab or sunitinib with the novel CXCR4 antagonist, PRX177561, would have superior antitumor activity.MethodsThe effects of bevacizumab, sunitinib, and PRX177561 were tested alone or in combination in subcutaneous xenografts of U87MG, U251, and T98G cells as well as on intracranial xenografts of luciferase tagged U87MG cells injected in CD1-nu/nu mice. Animals were randomized to receive vehicle, bevacizumab (4 mg/kg iv every 4 days), sunitinib (40 mg/kg po qd), or PRX177561 (50 mg/kg po qd).ResultsThe in vivo experiments demonstrated that bevacizumab and sunitinib increase the in vivo expression of CXCR4, SDF-1α, and TGFβ1. In addition, we demonstrate that the co-administration of the novel brain-penetrating CXCR4 antagonist, PRX177561, with bevacizumab or sunitinib inhibited tumor growth and reduced the inflammation. The combination of PRX177561 with bevacizumab resulted in a synergistic reduction of tumor growth with an increase of disease-free survival (DSF) and overall survival (OS), whereas the combination of PRX177561 with sunitinib showed a mild additive effect.ConclusionsThe CXC4 antagonist PRX177561 may be a valid therapeutic complement to anti-angiogenic therapy, particularly when used in combination with VEGF/VEGFR inhibitors. Therefore, this compound deserves to be considered for future clinical evaluation.

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Antitumor Effect of NK012, a 7-Ethyl-10-Hydroxycamptothecin–Incorporating Polymeric Micelle, on U87MG Orthotopic Glioblastoma in Mice Compared with Irinotecan Hydrochloride in Combination with Bevacizumab

Cited by 35 publications

References 25 publications

Detailed Distribution of NK012, an SN-38–Incorporating Micelle, in the Liver and Its Potent Antitumor Effects in Mice Bearing Liver Metastases

Detailed Distribution of NK012, an SN-38–Incorporating Micelle, in the Liver and Its Potent Antitumor Effects in Mice Bearing Liver Metastases

The Use of Longitudinal 18F-FET MicroPET Imaging to Evaluate Response to Irinotecan in Orthotopic Human Glioblastoma Multiforme Xenografts

The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma

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