Pharmacokinetics of Chiral Dendrimer-Triamine-Coordinated Gd-MRI Contrast Agents Evaluated by in Vivo MRI and Estimated by in Vitro QCM

Recently, we developed novel chiral dendrimer-triamine-coordinated Gd-MRI contrast agents (Gd-MRI CAs), which showed longitudinal relaxivity (r1) values about four times higher than that of clinically used Gd-DTPA (Magnevist®, Bayer). In our continuing study of pharmacokinetic differences derived from both the chirality and generation of Gd-MRI CAs, we found that the ability of chiral dendrimer Gd-MRI CAs to circulate within the body can be directly evaluated by in vitro MRI (7 T). In this study, the association constants (Ka) of chiral dendrimer Gd-MRI CAs to bovine serum albumin (BSA), measured and calculated with a quartz crystal microbalance (QCM) in vitro, were found to be an extremely easy means for evaluating the body-circulation ability of chiral dendrimer Gd-MRI CAs. The Ka values of S-isomeric dendrimer Gd-MRI CAs were generally greater than those of R-isomeric dendrimer Gd-MRI CAs, which is consistent with the results of our previous MRI study in vivo

13C/15N‐Enriched L‐Dopa as a Triple‐Resonance NMR Probe to Monitor Neurotransmitter Dopamine in the Brain and Liver Extracts of Mice

In an attempt to monitor μM-level trace constituents, we applied here 1H-{13C-15N} triple-resonance nuclear magnetic resonance (NMR) to 13C/15N-enriched L-Dopa as the inevitable precursor of the neurotransmitter dopamine in the brain. The perfect selectivity (to render endogenous components silent) and μM-level sensitivity (700 MHz spectrometer equipped with a cryogenic probe) of triple-resonance allowed the unambiguous and quantitative metabolic and pharmacokinetic analyses of administered L-Dopa/dopamine in the brain and liver of mice. The level of dopamine generated in the brain (within the range 7–76 μM, which covers the typical stimulated level of ~30 μM) could be clearly monitored ex vivo, but was slightly short of the detection limit of a 7T MR machine for small animals. This work suggests that μM-level trace constituents are potential targets of ex vivo monitoring as long as they contain N atom(s) and their appropriate 13C/15N-enrichment is synthetically accessible

Photoacoustic in vivo 3D imaging of tumor using a highly tumor-targeting probe under high-threshold conditions

Three-dimensional (3D) representation of a tumor with respect to its size, shape, location, and boundaries is still a challenge in photoacoustic (PA) imaging using artificial contrast agents as probes. We carried out PA imaging of tumors in mice using 800RS-PMPC, which was obtained by coupling of 800RS, a near-infrared cyanine dye, with PMPC, a highly selective tumor-targeting methacrylate polymer having phosphorylcholine side chains, as a probe. The conjugate 800RS-PMPC forms compact nanoparticles (dDLS = 14.3 nm), retains the biocompatibility of the parent polymer (PMPC) and exhibits unprecedented PA performance. When applied to mice bearing a 6 × 3 × 3 mm3 tumor buried 6 mm beneath the skin, the probe 800RS-PMPC selectively accumulates in the tumor and emits PA signals that are strong enough to be unambiguously distinguished from noise signals of endogenous blood/hemoglobin. The PA image thus obtained under high-threshold conditions allows 3D characterization of the tumor in terms of its size, shape, location, and boundaries

TGF-β-dependent reprogramming of amino acid metabolism induces epithelial–mesenchymal transition in non-small cell lung cancers

Epithelial–mesenchymal transition (EMT)—a fundamental process in embryogenesis and wound healing—promotes tumor metastasis and resistance to chemotherapy. While studies have identified signaling components and transcriptional factors responsible in the TGF-β-dependent EMT, whether and how intracellular metabolism is integrated with EMT remains to be fully elucidated. Here, we showed that TGF-β induces reprogramming of intracellular amino acid metabolism, which is necessary to promote EMT in non-small cell lung cancer cells. Combined metabolome and transcriptome analysis identified prolyl 4-hydroxylase α3 (P4HA3), an enzyme implicated in cancer metabolism, to be upregulated during TGF-β stimulation. Further, knockdown of P4HA3 diminished TGF-β-dependent changes in amino acids, EMT, and tumor metastasis. Conversely, manipulation of extracellular amino acids induced EMT-like responses without TGF-β stimulation. These results suggest a previously unappreciated requirement for the reprogramming of amino acid metabolism via P4HA3 for TGF-β-dependent EMT and implicate a P4HA3 inhibitor as a potential therapeutic agent for cancer

Analysis of DOC and Ram for NSCLC

Background: Current clinical trials demonstrated that combination regimens comprising chemotherapy and immunotherapy lead to better patient outcomes compared to chemotherapy alone as the first line of treatment for non-small cell lung cancer (NSCLC). In addition, the combination therapy of docetaxel (Doc) and ramucirumab (Ram) was considered one of the standard treatments for advanced or relapsed NSCLC patients. However, little is known about the therapeutic responders of this combination therapy among previously treated NSCLC patients. In the present study, we aimed to identify predictive factors for therapeutic response, including programmed death-ligand 1 (PD-L1) expression in tumors, for Doc treatment in combination with Ram. Methods: We retrospectively analyzed a total of 135 advanced or relapsed NSCLC patients who were refractory to platinum-based chemotherapy at eleven institutions in Japan between July 2016 and November 2018. Results: Our observations showed that PD-L1 expression in tumors is not associated with the efficacy of combined therapy of Doc and Ram in previously treated NSCLC patients. Analysis of the patient clinical profiles indicated that prior treatment with immune checkpoint inhibitors (ICIs) is a reliable predictor for the good progression-free survival (PFS) to this combination therapy (P=0.041). Conclusions: Our retrospective study indicated that combination regimens comprising chemotherapy and ICIs followed by Doc and Ram could be an optimal therapeutic option for NSCLC patients regardless of the PD-L1 status of tumors. Further investigations are required to strengthen clinical evidence demonstrating the effectiveness of the combination therapy of Doc plus Ram in previously treated NSCLC patients

Combined chemotherapy with carboplatin plus irinotecan showed favorable efficacy in a patient with relapsed small cell carcinoma of the prostate complicated with meningeal carcinomatosis

金沢大学附属病院がん高度先進治療センター金沢大学がん研究所分子標的がん医療研究開発センターWe report the case of a 65-year-old man with recurrent prostate cancer who presented with meningeal carcinomatosis. In September 2007, he had been diagnosed with mixed type small cell carcinoma and adenocarcinoma at clinical stage T4N1M1 (primary prostate tumor with multiple bone, liver, and lymph node metastases) and hormonal therapy had been administered. Following an increase in the level of pro-gastrin-releasing peptide (ProGRP), combined chemotherapy with cisplatin plus etoposide was implemented and showed efficacy in targeting the small cell carcinoma. In March 2008, he presented with signs of meningeal irritation; his condition deteriorated quickly and multiple brain metastases were confirmed by magnetic resonance imaging (MRI). A sample of cerebrospinal fluid collected by lumbar puncture showed cancer cells and an elevated level of ProGRP. Small cell carcinoma of the prostate complicated with meningeal carcinomatosis was diagnosed. A different chemotherapy regimen was then administered, consisting of a combination of carboplatin plus irinotecan, which is one of the most common first-line treatments for extensive-stage small cell lung carcinoma. From day 20 after the initiation of this therapy, he gradually recovered from the signs of meningeal irritation, and brain MRI showed nearly normal findings; also, the serum level of ProGRP was reduced. In conclusion, we report the efficacy of combined treatment with carboplatin plus irinotecan for small cell carcinoma of the prostate complicated with meningeal carcinomatosis. Because this clinical condition is extremely rare, a gold standard treatment has yet to be established. © 2009 Japan Society of Clinical Oncology

Metastatic renal cell carcinoma complicated with diffuse alveolar hemorrhage: a rare adverse effect of sunitinib

金沢大学附属病院がん高度先進治療センターWe report the case of a 67-year-old man with metastatic papillary renal cell carcinoma (RCC) who developed bloody sputum after the administration of sunitinib. Chest computed tomography revealed diffuse ground-glass opacity lesions, and bloody bronchoalveolar lavage fluid was obtained by flexible bronchoscopy. The abnormal shadows promptly regressed after withdrawal of sunitinib. In four cycles of sunitinib treatment, he suffered from controllable diffuse alveolar hemorrhage. Finally, he died of respiratory failure 8 months after onset. This is the first case report of diffuse alveolar hemorrhage as an adverse effect of sunitinib in metastatic papillary RCC. Care should be taken with pulmonary hemorrhage in the use of anti-angiogenesis agents in not only squamous cell lung cancer, but also metastatic lung tumors. © 2010 Japan Society of Clinical Oncology

DNA ブンシナイ 5 - メチルシトシン エンキ ノ ナフトキノン ゾウカン ヒカリ イチデンシ サンカ ハンノウ ト DNA メチルカ ブンセキ エ ノ オウヨウ ニ カンスル ケンキュウ

京都大学0048新制・課程博士博士(工学)甲第13838号工博第2942号新制||工||1434(附属図書館)UT51-2008-C754京都大学大学院工学研究科物質エネルギー化学専攻(主査)教授 西本 清一, 教授 大江 浩一, 教授 青山 安宏学位規則第4条第1項該当Doctor of EngineeringKyoto UniversityDA

Synthesis and photooxidation of oligodeoxynucleotides containing 5-dimethylaminocytosine as an efficient hole-trapping site in the positive-charge transfer through DNA duplexes.

We have designed and synthesized DNA duplexes containing 5-dimethylaminocytosine ((DMA)C) to investigate the effects of C(5)-substituted cytosine bases on the transfer and trapping of positive charge (holes) in DNA duplexes. Fluorescence quenching experiments revealed that a (DMA)C base is more readily one-electron oxidized into a radical cation intermediate as compared with other natural nucleobases. Upon photoirradiation of the duplexes containing (DMA)C, the photosensitizer-injected hole migrated through the DNA bases and was trapped efficiently at the (DMA)C sites, where an enhanced oxidative strand cleavage occurred by hot piperidine treatment. The (DMA)C radical cation formed by hole transfer may undergo specific hydration and subsequent addition of molecular oxygen, thereby leading to its decomposition followed by a predominant strand cleavage at the (DMA)C site. This remarkable property suggests that the modified cytosine (DMA)C can function as an efficient hole-trapping site in the positive-charge transfer in DNA duplexes