PHARMACOKINETIC STUDY OF INTRAPERITONEALLY ADMINISTERED ETOPOSIDE AGAINST PERITONITIS CARCINOMATOSA

Etoposide is becoming important in primary and salvage therapy for ovarian cancer. In the present study, we administered etoposide (100-300 mg/subject) intraperitoneally to six patients suffering from cancerous peritonitis, particularly that resulting from ovarian cancer, to investigate the bioavailability and pharmacokinetics of this drug. The peak etoposide level in the ascites was 80 μg/ml. Twelve hours after intrapertoneal administration (i. p.), more than 10 μg/ml of etoposide was still found in ascites. The serum level after administration of 100 mg i. p. reached approximately 4 μg/ml within 30 minutes, and 1 μg/ml of etoposide was still found in serum after 24 hours. The etoposide levels in ascites and serum after 300 mg i. p. were higher than those after 100 mg i. p. When the peritoneum was intact, the area under the curve (AUC) of etoposide in ascites was low (164 μg・h/ml), and the peritoneal clearance (Clp) was high. In contrast, in advanced cancerous peritonitis, the AUC in ascites was high (500 μg・h./ml) and the Clp was low. The AUC of etoposide in the ascites of patients with cancerous peritonitis was more than five-fold greater than that of patients with an intact peritoneum, while MRT (mean residence time) was 15-fold, and VRT (variance of residence time) was 300-fold greater. The AUC ratio in intact peritoneum was 4.1, and that in cancerous peritonitis ranged from 17.8 to 27.1. AUC, MRT and VRT of etoposide transported into the blood were slightly higher in advanced cases than in those with intact peritoneum. These findings indicate that intraperitoneal etoposide han not only a direct anticancer effect in the abdominal cavity but also shows effects via the vascular system of the tumor

IN VITRO CYTOTOXICITY OF CPT-11 (SN-38) ALONE AND IN COMBINATION WITH CISPLATIN ON OVARIAN CANCER CELLS

We investigated the in vitro cytotoxic effects of CPT-11, a new derivative of camptothecin, and its metabolizable form in vivo, SN-38, on cisplatin-resistant (SHIN-3) and -sensitive (MN-1) ovarian cancer cell lines using the MTT assay. We also attempted to identify the optimal schedule of administration for cisplatin combined with low-dose continuous exposure to CPT-11 (3 μg/ml) or SN-38 (5 ng/ml). With either CPT-11 or SN-38 alone, a marked schedule-dependent inhibition of growth was obtained with exposure for over 40 hours to concentrations of those agents applicable to clinical use (CPT-11 : <7.58 μg/ml, SN-38 : <72 ng/ml), even in a cisplatin-resistant cell line. Increasing the assay AUC of these agents only by dose escalation did not enhance cytotoxity with both MN-1 (CPT-11 : 3-50 μg/ml, SN-38 : 2.16-72 ng/ml) and SHIN-3 (CPT-11 : 5-50 μg/ml, SN-38 : 21.6-720 ng/ml) cell lines up to 72 hours of exposure. Pretreatment of SHIN-3 cells with either CPT-11 (3 μg/ml) or SN-38 (5 ng/ml) for 48 hours before the administration of cisplatin (4-20 μg/ml) appeared to produce an inhibition which exceeded that produced by either a longer (96 hours) or shorter (0 hour) pretreatment with them. Flow cytometric analysis showed that treatment with CPT-11 and SN-38 in SHIN-3 cell line was associated with a peak in G₂/M phase at 24 hours and an increase in the G₀/G₁ phase fraction for up to 96 hours. It is thus suggested that the continuous administration of a low dose of CPT-11 or of SN-38 may be useful clinically. The in vitro cytotoxicity of cisplatin could be increased by pretreatment with either CPT-11 or SN-38

Current status of tertiary debulking surgery and prognosis after secondary debulking surgery for recurrent Müllerian epithelial cancer in Japan: a retrospective analysis of 164 patients (KCOG-G1402)

BackgroundThis study aimed to evaluate the current status of secondary debulking surgery (SDS) and tertiary debulking surgery (TDS; performed for recurrence after SDS) and to assess the overall survival after recurrence of Müllerian epithelial cancer in Japan. We also evaluated the data of patients who underwent a fourth debulking surgery (i.e., quaternary debulking surgery (QDS)).MethodsWe conducted a retrospective study of 164 patients with recurrent Müllerian epithelial cancers (i.e., ovarian, tubal, and peritoneal cancers). The SDS was performed between January 2000 and September 2014 in 20 Japanese hospitals. Clinicopathological data were collected and analyzed.ResultsOf the 164 patients, 66 patients did not have a recurrence or died after SDS. Ninety-eight patients had a recurrence after SDS. Forty-three of the 98 patients underwent TDS; 55 of the 98 patients did not undergo TDS and were classified into the non-TDS group. The overall survival (OS) after SDS was significantly better in the TDS group than in the non-TDS group. The median OS after SDS was 123 and 42 months in the TDS group and non-TDS group, respectively. Of the 43 patients who received TDS, 11 patients were further treated with QDS. The median OS after SDS was 123 months for patients who underwent QDS.ConclusionsThis multicenter study on the prognosis of post-SDS is apparently the first report on QDS in Japan. Patients undergoing TDS have a good prognosis, compared to patients in the non-TDS group. Novel drugs are being evaluated; however, debulking surgery remains a necessary treatment for recurrence

〈Original〉Enhanced cartilage regeneration by slow-release of basic fibroblast growth factor impregnated in gelatin microspheres

[Abstract]cartilage graft is used for various reconstructions in the plastic surgery field. Auricular and costal cartilages are generally harvested, and the amount of collectable cartilage is often limited. The optimal utilization of collected cartilage to maximize the effect of cartilage graft has always been attempted resulting in unfavorable donor deformity with pain when harvest volume is large. Tissue reconstruction with minimizing donor site sacrifice is the ideal method. In this study, we introduced a bFGF slow-release system on a cartilage disk and investigated the possibility of uantitatively growing cartilage in a large animal model