Ken Aoki

Inactivation of cis-diamminedichloroplatinum (II) in blood and protection of its toxicity by sodium thiosulfate in rabbits.

SummaryThe mode of inactivation of cis-diamminedichloroplatinum(II) (DDP) in the bloodstream and protection from its toxicity by sodium thiosulfate (STS) were investigated in rabbits.Plasma ultrafiltrate in rabbits given 5 mg/kg DDP IV and various excess molar ratios of STS IV were assayed for the active platinum levels with a new microbiological assay system using an E. coli strain. The active platinum species in the plasma were inactivated completely by coadministration of a 400-fold excess of STS IV. The rabbits were almost completely protected against both BUN increase and body weight loss normally caused by DDP when 400-fold doses of STS were given. Diuretic effects were also observed.Our data provide evidence for the basis of optimum use of STS to protect against DDP toxicity. [6, 9]. This TRC with DDP and STS is now in clinical trial [7, 8], but the precise mode of protective action of STS against DDP toxicity has not been determined.We now present evidence that this protective effect is due to inactivation of biologically active DDP in the bloodstream.

A synthesized 3DCG contents generator using IEC framework

A synthetic approach to effectively support 3D computer graphics (3DCG) authoring is proposed. Interactive evolutionary computation (IEC) has been applied for the 3D authoring domain and proven to be useful for easily generating aesthetic 3DCG contents even for the novices. The previous systems, however, only focus on a specific subtask out of a whole 3DCG production process. All dominant tasks in the 3DCG production such as geometric modeling, rendering, animation, and 3D data management are covered in our approach. The proposed method reorganizes a monolithic IEC system into a combination of front-end IEC explorer and back-end graphics engines. Because it works on the Internet, some critical applications such as digital prototyping and e-learning come within the range.

Rituximab does not compromise the mobilization and engraftment of autologous peripheral blood stem cells in diffuse-large B-cell lymphoma

To investigate effects of the preautografting administration of rituximab on the mobilization and engraftment of peripheral blood stem cells (PBSC), we retrospectively analyzed the outcomes of 43 newly diagnosed diffuse-large B-cell lymphoma patients who received CHOP chemotherapy with or without rituximab as a first-line treatment before autologous PBSC transplantation (PBSCT). There was no difference in the number of CD34+ cells among PBSC between the non-rituximab and the rituximab groups. Although B-cells were completely depleted from PBSC in the rituximab group, we found no difference in the expression of CXCR-4, VLA-4 and c-Kit on PBSC, indicating that rituximab did not affect the expression of these adhesion molecules, which might be involved in the mechanism of mobilization. There was no significant difference in the recovery of neutrophils and platelets, transplant-related toxicity and post-transplant complications between the two groups. Despite the short follow-up, there was no significant difference in progression-free survival between the two groups. These results indicated no adverse effect of rituximab on the mobilization and engraftment of PBSC. Larger studies are required to determine the impact of rituximab on the mobilization and function of PBSC as well as whether a survival advantage exists in patients who undergo auto-PBSCT with rituximab.

Upper hemibody infusion ofcis-diamminedichloroplatinum (II) followed by systemic antidote, sodium thiosulfate, for lung metastasis in rats

Effects of a combination chemotherapy using cis-diamminedichloroplatinum (II) (DDP) and its antidote, sodium thiosulfate (STS), on metastatic lung tumour in rats were studied.Rats were given an upper hemibody infusion (UHI) of 15 mg/kg DDP immediately after occlusion of the abdominal aorta and i.v. administration of 1581 mg/kg STS (200-fold molar ratio to DDP) 10 min later. The aortic clamp was released at approximately 11 min after the beginning of UHI when a half volume of STS solution was infused. Antitumour and side effects in this group were compared with those in the respective control groups given 5 mg/kg DDP alone by UHI or by systemic administration.In the group given UHI of DDP (DDP-UHI) in combination with STS, there was a significantly better antitumour effect than seen in the group given DDP alone, as evaluated by the number of lung tumour nodules and survival time after inoculation of the transitional cell carcinoma into the lung. Nephrotoxicity, as assessed by increase in BUN levels, was completely avoided. Haematological toxicity effects assessed by decreases in WBC were slight but body-weight loss due to anorexia was severe.

Applicability of interactive evolutionary computation to mental health measurement

We show experimentally the applicability of interactive evolutionary computation (IEC) to a new application field, mental health measurement. We had 3 schizophrenics and 5 mentally healthy students design happy and sad impression computer graphics (CG) fighting images using IEC and asked other 33 students to evaluate the CG images using Scheffes method of paired comparison. Statistical tests of the evaluations showed that the range of emotional impressions perceived by the three schizophrenics between happy-sad was significantly narrower than that which was perceived by the mentally healthy students (p < 0.01). This experimental result implies that IEC has potential to contribute to psychiatry, and it also showed the possibility to expand IEC applicability beyond conventional system optimization and to a new area, mental health measurement.

“Two-route chemotherapy” using cis-diamminedichloroplatinum(II) and its antidote, sodium thiosulfate, combined with angiotensin II is effective against peritoneally disseminated cancer in rats

Summary“Two-route chemotherapy” (TRC) using cis-diamminedichloroplatinum(II) (DDP) and its antidote, sodium thiosulfate (STS), combined with the angiotensin II (AT-II)-induced hypertension method was evaluated for its efficacy against peritoneally disseminated tumors in rats. A bolus i.p. injection of DDP (15 mg/kg) was given 1 min after the initiation of an AT-II (16.5 μg/kg) i.v. infusion lasting 11 min. Immediately after the termination of the AT-II infusion, 1,580 mg/kg STS was injected i.v. over a further 5 min. This modified TRC significantly improved the antitumor effect, evaluated by survival (increase in life span, 273%), compared with that achieved with other treatments, as follows: 15 mg/kg DDP i.p. and the concomitant i.v. infusion of 1,580 mg/kg STS (conventional TRC), 153% increase in life span; 5 mg/kg DDP i.p. with or without AT-II i.v. (167% and 107% increases in life span, respectively). As an index of nephrotoxicity, blood urea nitrogen (BUN) levels seen after modified TRC (21.1 mg/dl) were as low as those observed after conventional TRC (19.1 mg/dl), despite the postadministration of STS, and were much lower than those seen after DDP alone or DDP plus AT-II (35.6 and 35.7 mg/dl, respectively). Further evaluation of the effectiveness of modified TRC using various doses of DDP gave similar results. The feasibility of the administration of STS 10 min after DDP treatment was explained by the significant inhibition of DDP delivery to the kidney during the AT-II-induced hypertension. Thus, TRC combined with AT-II has a superior therapeutic effect against peritonitis carcinomatosa induced in rats.

“Two route infusion chemotherapy” usingcis-diamminedichloroplatinum (II) and its antidote, sodium thiosulfate, for metastatic liver tumors in rats

We studied the effects of combination chemotherapy of an antitumor drugcis-diamminedichloroplatinum (II) (DDP) and its potent antidote, sodium thiosulfate (STS) in rat liver tumor systems. This therapy was given to female WKA rats with metastatic liver tumors 13 days after inoculation of syngeneic hepatoma cells through the mesenteric vein. DDP and STS were administeredvia two different routes, hepatic artery and femoral vein, respectively (we call this treatment “two route infusion chemotherapy”). The antitumor effects were evaluated 21 days after the treatment by calculating the tumor weight from the total weight of the liver. Tumor weights of rats treated with 20 mg/kg of intra-arterial DDP plus 1,054 mg/kg of systemic STS (group A), 5 mg/kg of intra-arterial DDP alone (group B), and 5 mg/kg of systemic DDP alone (group C) were, about one fifth two fifths and three fifths of the tumor weights in the untreated controls, respectively. In group A, no rats died despite administration of a 4-fold higher DDP dose than in the latter two groups B and C in which 14–18 per cent of the rats died, due to DDP-induced toxicity. The patterns of body weight gain in the three groups after the chemotherapy were much the same. Our results clearly indicate that the antitumor effect of DDP on metastatic liver tumors in rats can remarkably be enhanced by the “two route infusion chemotherapy” of DDP and STS.

Efficacy of two-route chemotherapy using intraperitoneal neocarzinostatin and its antidote, intravenous tiopronin, for peritoneally disseminated tumors in mice.

We assessed the efficacy of “two‐route chemotherapy (TRC)” using neocarzinostatin (NCS) given ip and its antidote, N‐(2‐mercaptopropionyl)‐glycine (tiopronin), given iv for peritoneally disseminated tumors in mice. Whether or not the single iv administration of tiopronin (800 mg/kg) at various times after NCS ip would decrease the lethal toxicity induced by NCS ip was given attention. When compared with the LD50 (4.4 mg/kg) of NCS ip alone, simultaneous or postadministration of tiopronin together with NCS ip increased the LD50 of NCS ip by 2.8 to 7.6 fold in a time‐dependent manner. Chemotherapy experiments on ip disseminated tumors in mice were done to compare the antitumor effects of the following treatments, at two dose levels (75 and 100% of LD10) of NCS, with or without tiopronin: treatment with NCS ip alone and combined chemotherapy using NCS ip plus tiopronin iv, simultaneously or postadministered. Based on the survival time of the treated mice, the groups given NCS plus tiopronin (postadministration, 15 or 25 min later) showed a significantly superior survival time to that of the group given NCS ip alone. The side effects, evaluated in terms of the changes in body weight and number of WBC of the mice, were not significantly different among the groups treated with 100% of LD10 of NCS.

Increased therapeutic effect on metastatic liver tumors in rats of two-route chemotherapy usingcis-diamminedichloroplatinum (II) and its antidote, sodium thiosulfate, with temporary clamping of the abdominal aorta

SummaryTo improve the therapeutic effects of conventional “two-route chemotherapy” (TRC) comprisingcis-diamminedichloroplatinum(II) (CDDP) given via the hepatic artery plus simultaneous i. v. sodium thiosulfate (STS) on metastatic liver tumors in rats, we combined TRC with aortic clamping at the supraceliac level. Treatments were evaluated in Wistar-King-Aptekman (WKA) rats bearing metastatic liver tumors 7 days after the inoculation of 106 syngenic RBT-1 (transitional-cell carcinoma) cells via the mesenteric vein. When 15 mg/kg CDDP was injected i. a. over 5 min, immediately followed by STS 1,580 mg/kg (200-fold the molar equivalent of 15 mg/kg CDDP) given i. v. over a further 5 min, the antitumor activity, evaluated by the number of tumor nodules present 12 days after treatment, was superior to that of conventional TRC (15 mg/kg i. a. CDDP plus simultaneous administration of 1,580 mg/kg i. v. STS), but the blood urea nitrogen (BUN) level was highly elevated (63.6 mg/dl). With aortic clamping for 7.5 min during CDDP administration and the first half of STS treatment, the TRC consisting of CDDP plus delayed STS (modified TRC) exhibited a further improvement in antitumor activity, with no nephrotoxicity (BUN, 17.1 mg/dl). Although the antitumor activity of 3 or 5 mg/kg i. a. CDDP was also increased by aortic clamping, in animals with normal BUN levels the survival of those treated with modified TRC was greater than that of rodents given 3 mg/kg i. a. CDDP with aortic clamping; however, the former was the same as that of animals given 5 mg/kg i. a. CDDP with aortic clamping whose BUN levels were elevated (31.2 mg/dl). Loss of body weight, the decrease in WBC counts, and changes in the serum transaminase levels in rats given modified TRC were tolerable. The improved therapeutic effect of modified TRC can be explained as follows: during aortic clamping, (a) CDDP delivery to the kidney decreased by 96% and made feasible the delay in STS administration after CDDP without nephrotoxicity, and (b) CDDP retention in the liver was increased by 366%, as aortic clamping decreased the portal blood flow, thereby inhibiting the washout of CDDP from the liver.

“Two-route chemotherapy” using high-dose intra-arterial neocarzinostatin and systemic tiopronin, its antidote, for rat limb tumor

SummaryWe studied the effect of “two-route chemotherapy” (TRC) with intra-arterial (IA) neocarzinostatin (NCS) and IV N-(2-mercaptopropionyl)-glycine (tiopronin), its antidote, on rat limb tumors. Chemotherapy experiments were carried out on day 9 after the inoculation of 106 syngeneic transitional carcinoma cells into the hind limb in female Wistar King A rats. In the group given TRC, 3500 units/kg NCS and 800 mg/kg tiopronin were given via the femoral artery and the femoral vein, respectively. The antitumor effect was evaluated by the tumor weight on day 12 after the treatment. Compared with the weight of tumors in untreated controls, TRC reduced tumor weight to one-tenth, while 700 units/kg IA NCS alone reduced tumor weight to one-third and 700 units/kg systemic NCS alone reduced tumor weight to three-fourths of the control weight. In the group given TRC, WBC and nucleated bone marrow cells were completely protected and loss of body weight was slight.