The ovaries attenuate the aggravating effect of testosterone on glomerular injury in Adriamycin-induced nephropathy of female rats.

To clarify whether the ovaries have a potential to attenuate the aggravating effect of testosterone (T) on glomerular injury, we investigated the effect of T in female rats with or without ovaries, using Adriamycin (ADR)-induced nephropathy in female Sprague-Dawley rats. Group 1 consisted of female control rats, group 2 received T, groups 3 and 4 were subjected to ovariectomy (OVX) at 5 weeks of age, and group 4 received further T treatment. Group 5 consisted of male control rats. T was injected subcutaneously every 4 weeks from 5 weeks of age through the end of the experiment. ADR 2 mg/kg was administered intravenously to all rats twice, at 8 weeks of age and 20 days later. Body weight, blood pressure, urinary protein and serum constituents were investigated every 4 weeks from 4 through 24 weeks after the second ADR injection. Each group was studied morphologically 24 weeks after the second ADR injection. Treatment with T or with OVX and T significantly increased the urinary protein excretion. OVX had no significant effect on the urinary protein excretion. Treatment with either T or OVX did not induce any significant effects on the renal function with regard to blood urea nitrogen (BUN), serum creatinine (Cr) and Cr clearance (Ccr) levels, but a combined treatment with OVX and T significantly lowered the serum albumin levels, increased the levels of BUN and Cr and lowered the Ccr values. The glomerulosclerosis index was significantly and markedly higher in control male rats than in control females. Treatment with T resulted in a slight but significant increase in glomerular injury to levels similar to those seen in ovariectomized rats. Combined treatment with OVX and T significantly aggravated glomerular injury in a somewhat accelerated manner, associated with a significant increase in glomerular tuft volume. Our results suggested that the ovaries could not completely suppress glomerular injury worsened by T administered at serum levels similar to those of male rats, but they had a potential to attenuate glomerular injury induced by T, and the protective effect of the ovaries on glomerular injury may be related to their attenuating effect on glomerular growth.

[Antitumor activities of oily suspended YM881 (SMANCS) against VX2 carcinoma].

YM881 (MW 15,000) is a conjugate protein preparation of two copolymer of styrene-maleic acid [SMA] (MW 1,500) and neocarzinostatin [NCS] (MW 12,000). Antitumor activities of YM881 and NCS with or without oily solvent injected arterially against VX2 carcinoma of rabbits were examined. Based on the growth and histological examination of the tumor, remarkable anti-tumor activities were observed with oily suspended YM881 but not with the other group. This results indicate that targeting of the anticancer agent to the tumor is most important for eliciting of antitumor activities.

[Arterial administration of oily anticancer agents dissolved in lipiodol fluid in recurrence of hepatoma after hepatic resection and in metastatic liver cancer].

Oily anticancer agents such as SMANCS dissolved in Lipiodol fluid (Lipiodol) were administered to 18 patients with recurrence of hepatocellular carcinoma after hepatic resection and to 87 patients with metastatic liver cancer. The following results were obtained. i) It was proved and to that Lipiodol worked as a carrier of anticancer drugs and that targeting chemotherapy could be achieved. ii) The serum AFP level and tumor size showed a decrease in 91% and 87% of patients with recurrence of hepatoma, respectively. iii) This method could be applied to extrahepatic metastasis of hepatoma, and anticancer activity was also observed in these lesions. iv) The serum CEA level was decreased in 53 patients (83%) and reduction of tumor size was observed in 32 patients (46%) with metastatic liver cancer. v) In 5 out of 7 tumors resected after arterial injection of oily anticancer agents, necrosis was found histologically in over 95% of the tumor.

Anticancer effects of arterial administration of the anticancer agent SMANCS with lipiodol on metastatic lymph nodes.

A new method of arterially administering an oily anticancer agent was successfully established for the selective targeting of metastatic lymph nodes. A high molecular weight anticancer agent, a conjugate of copolymer (styrene maleic acid) to neocarzinostatin (SMANCS) was prepared in our laboratory and dissolved in a lymphographic oily contrast medium, Lipiodol (SMANCS/Lipiodol). SMANCS/Lipiodol was administered intraoperatively to eight patients with colorectal cancer and preoperatively to one patient with gastric cancer with lymph node metastases. In six of the patients with colorectal cancer, the drug was administered via an artery and in the other two patients the drug was injected into the wall of the colon near the primary cancer. In the patient with gastric cancer, the drug was administered via the left gastric artery. Delivery of the drug to the lymph nodes was examined roentgenologically and the anticancer effect was examined histologically. The results showed that SMANCS/Lipiodol could be delivered to the metastatic lymph node via the artery, but it could not be delivered to the metastatic lesion of the lymph node via the lymphatic route. In the patient with gastric cancer, SMANCS/Lipiodol preoperatively administered via an artery was found to remain selectively in a metastatic lymph node and an anticancer effect was histologically proved in all three of the metastatic lymph nodes.

[Targeting of anticancer chemotherapy utilizing the characteristic nature of the neovasculature of solid tumors].

We have been able to achieve targeting of anticancer treatments using the differences between the neovasculature of solid tumors and the vasculature of normal tissues. The first of these differences was as follows; We discovered that when the lipid contrast medium, Lipiodol, was administered arterially, it remained selectively in the solid tumor for a long time. Using this characteristic nature of Lipiodol, we achieved targeting of anticancer chemotherapy by arterial administration of oily anticancer drugs solubilized in Lipiodol. Remarkable anticancer effects against various malignant solid tumors were observed using this targeting chemotherapy. The second of the above differences, studied by Suzuki, is responsiveness to angiotensin II, in which the blood flow in the tumor can be increased using this vasoconstrictor. With Angiotensin II, a larger volume of oily anticancer drugs could be delivered to the tumor. The third difference is the permeability of the neovasculature to drugs of high molecular weight and the duration that these drugs remain in the extracapillary space. The high-molecular-weight anticancer agent, SMANCS (m.w. 17,000) dissolved in 5% glucose solution, was administered intravenously, and its histological antitumor effects on gastric cancer and esophageal cancer were clearly observed.