In spite of the clinical usefulness of cisplatin (CDDP), there are many occasions in which it is difficult to continue the administration of CDDP due to its nephrotoxicity and neurotoxicity. We examined the incorporation of CDDP into polymeric micelles to see if this allowed the resolution of these disadvantages. Cisplatin was incorporated into polymeric micelles through the polymer -metal complex formation between polyethylene glycol poly(glutamic acid) block copolymers and CDDP (NC-6004). The pharmacokinetics, pharmacodynamics, and toxicity studies of CDDP and NC-6004 were conducted in rats or mice. The particle size of NC-6004 was approximately 30 nm, with a narrow size distribution. In rats, the area under the curve and total body clearance values for NC-6004 were 65-fold and one-nineteenth the values for CDDP (Po0.001 and 0.01, respectively). In MKN-45-implanted mice, NC-6004 tended to show antitumour activity, which was comparable to or greater than that of CDDP. Histopathological and biochemical studies revealed that NC-6004 significantly inhibited the nephrotoxicity of CDDP. On the other hand, blood biochemistry revealed transient hepatotoxicity on day 7 after the administration of NC-6004. Furthermore, rats given CDDP showed a significant delay (Po0.05) in sensory nerve conduction velocity in their hind paws as compared with rats given NC-6004. Electron microscopy in rats given CDDP indicated the degeneration of the sciatic nerve, but these findings were not seen in rats given NC-6004. These results were presumably attributable to the significantly reduced accumulation of platinum in nerve tissue when NC-6004 was administered (Po0.05). NC-6004 preserved the antitumour activity of CDDP and reduced its nephrotoxicity and neurotoxicity, which would therefore seem to suggest that NC-6004 could allow the long-term administration of CDDP where caution against hepatic dysfunction must be exercised.

7-Ethyl-10-hydroxy-camptothecin (SN-38), a biological active metabolite of irinotecan hydrochloride (CPT-11), has potent antitumor activity but has not been used clinically because it is a water-insoluble drug. For delivery by i.v. injection, we have successfully developed NK012, a SN-38-releasing nanodevice. The purpose of this study is to investigate the pharmacologic character of NK012 as an anticancer agent, especially in a vascular endothelial growth factor (VEGF)-secreting tumor model. The particle size of NK012 was f20 nm with a narrow size distribution. NK012 exhibited a much higher cytotoxic effect against lung and colon cancer cell lines as compared with CPT-11. NK012 showed significantly potent antitumor activity against a human colorectal cancer HT-29 xenograft as compared with CPT-11. Enhanced and prolonged distribution of free SN-38 in the tumor was observed after the injection of NK012. NK012 also had significant antitumor activity against bulky SBC-3/Neo (1,533

NK105 is a micellar nanoparticle formulation designed to enhance the delivery of paclitaxel (PTX) to solid tumours. It has been reported to exert antitumour activity in vivo and to have reduced neurotoxicity as compared to that of free PTX. The purpose of this study was to investigate the radiosensitising effect of NK105 in comparison with that of PTX. Lewis lung carcinoma (LLC)-bearing mice were administered a single intravenous (i.v.) injection of PTX or NK105; 24 h after the drug administration, a proportion of the mice received radiation to the tumour site or lung fields. Then, the antitumour activity and lung toxicity were evaluated. In one subset of mice, the tumours were excised and specimens were prepared for analysis of the cell cycle distribution by flow cytometry. Combined NK105 treatment with radiation yielded significant superior antitumour activity as compared to combined PTX treatment with radiation (P ¼ 0.0277). On the other hand, a histopathological study of lung sections revealed no significant difference in histopathological changes between mice treated with PTX and radiation and those treated with NK105 and radiation. Flowcytometric analysis showed that NK105-treated LLC tumour cells showed more severe arrest at the G2/M phase as compared to PTX-treated tumour cells. The superior radiosensitising activity of NK105 was thus considered to be attributable to the more severe cell cycle arrest at the G2/M phase induced by NK105 as compared to that induced by free PTX. The present study results suggest that further clinical trials are warranted to determine the efficacy and feasibility of combined NK105 therapy with radiation.

Background: The neutrophil-lymphocyte ratio (NLR) is a well-known prognostic marker in various cancers. However, its role as a predictive marker for the effectiveness of nivolumab in patients with metastatic RCC (mRCC) remains unclear. We evaluated the relationships between the NLR and progression-free survival (PFS) or overall survival (OS) in mRCC patients treated with nivolumab. Methods: The data of 52 mRCC patients who received nivolumab therapy were collected from seven institutes and evaluated. The median follow-up period from treatment with nivolumab was 25.2 months (IQR 15.5-33.2). Results: The median duration of nivolumab therapy was 7.1 months (IQR 2.9-24.4). The objective response rate was 25% and the 1-and 2-year PFS rates were 46.2 and 25.2%, respectively. The median NLR values at baseline and 4 weeks were 3.7 (IQR 2.7-5.1) and 3.3 (IQR 2.4-5.7), respectively. In the multivariate analysis, an NLR of ≥3 at 4 weeks was an independent predictor of PFS (P = 0.013) and OS (P = 0.034). The 1-year PFS of patients with an NLR of < 3 at 4 weeks was better than that of those with an NLR of ≥3 (75% versus 29%, P = 0.011). The 1-year OS of patients with an NLR of < 3 at 4 weeks was also better than that of those with an NLR of ≥3 (95% versus 71%, P = 0.020). Conclusions: Although the baseline NLR was not associated with PFS or OS, an NLR of ≥3 at 4 weeks after the initiation of therapy might be a robust predictor of poor PFS and OS in mRCC patients undergoing sequential treatment with nivolumab.

Background To evaluate the association of clinical outcomes with posttreatment changes in the relative eosinophil count (REC) and neutrophil-to-eosinophil ratio (NER) in patients with advanced urothelial cancer (UC) treated with pembrolizumab. Materials and Methods We retrospectively analyzed 105 patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy. The REC and NER before and three weeks after pembrolizumab were recorded. A receiver operating characteristic curve was used to determine the optimal cut-off values for analyzing the risk. Results There were no significant differences in the overall survival (OS) between the REC ≥4.8% and <4.8% groups and the NER ≥13.7 and <13.7 groups before pembrolizumab (p=0.997 and 0.669, respectively). However, a significant difference in the OS was confirmed between the increased and decreased REC groups and between the decreased and increased NER groups at 3 weeks after pembrolizumab (p<0.001 and 0.002, respectively). Multivariate analyses revealed that an Eastern Cooperative Oncology Group Performance Status ≥2 (P=0.003), albumin <3.7 g/dl (p=0.002), LDH >246 U/L (p=0.011), disease site ≥3 organs (p=0.019), decreased posttreatment REC (3 weeks later) (p=0.002) and increased posttreatment NER (3 weeks later) (p=0.022) were independent prognostic factors for a worse OS. Conclusion An increased REC and decreased NER after pembrolizumab may be significant early predictive markers of improved clinical outcomes in patients with advanced UC receiving pembrolizumab.