Rapid quasi-periodic oscillations in the relativistic jet of BL Lacertae.

Blazars are active galactic nuclei (AGN) with relativistic jets whose non-thermal radiation is extremely variable on various timescales1-3. This variability seems mostly random, although some quasi-periodic oscillations (QPOs), implying systematic processes, have been reported in blazars and other AGN. QPOs with timescales of days or hours are especially rare4 in AGN and their nature is highly debated, explained by emitting plasma moving helically inside the jet5, plasma instabilities6,7 or orbital motion in an accretion disc7,8. Here we report results of intense optical and γ-ray flux monitoring of BL Lacertae (BL Lac) during a dramatic outburst in 2020 (ref. 9). BL Lac, the prototype of a subclass of blazars10, is powered by a 1.7 × 108 MSun (ref. 11) black hole in an elliptical galaxy (distance = 313 megaparsecs (ref. 12)). Our observations show QPOs of optical flux and linear polarization, and γ-ray flux, with cycles as short as approximately 13 h during the highest state of the outburst. The QPO properties match the expectations of current-driven kink instabilities6 near a recollimation shock about 5 parsecs (pc) from the black hole in the wake of an apparent superluminal feature moving down the jet. Such a kink is apparent in a microwave Very Long Baseline Array (VLBA) image.

Pregnancy achieved following IVF-ET after surgery for infertility with perforate transverse vaginal septum and incomplete septate uterus: case report.

Transverse vaginal septum is a rare congenital anomaly. Imperforate transverse vaginal septum causes marked clinical symptoms, and is diagnosed at a young age in most cases. Perforate transverse vaginal septum is difficult to detect due to the absence of symptoms. In this study, we report a case of a 33-year-old infertile female with a perforate transverse vaginal septum and incomplete septate uterus who had wished to bear a child for over ten years, and consulted our hospital. Transverse vaginal septum was considered to be an etiological factor for infertility. After surgery for transverse vaginal septum, in vitro fertilization achieved pregnancy.

The effect of dietary polyunsaturated fatty acid on insulin sensitivity and lipid metabolism in Otsuka Long-Evans Tokushima Fatty (OLETF) rats.

The effects of insulin sensitivity and lipid metabolism of dietary lard, eicosapentaenoic acid-rich oil (EPA oil) or arachidonic acid oil (AA oil) in Otsuka Long-Evans Tokushima Fatty (OLETF) rats were examined. Blood glucose was not different in each group at 30, 60, 120 min on an oral glucose tolerance test. Fasting blood glucose levels were lower in lard and AA oil groups than in controls. Hepatic triglyceride concentration and liver histochemistry revealed that the fat content was higher in the lard group and the AA oil group than in controls. The EPA oil group showed TG levels as high as the control group. Serum total cholesterol in the EPA oil group was lower, while the level in the AA oil group was higher than in the lard and control groups. HDL cholesterol was 1.5-fold higher in the AA oil group than in controls. Dietary EPA oil or AA oil supplementation showed different effects on lipid metabolism in this model.

An advantage for use of isotope labeling and NMR chemical shifts to analyze the structure of four homologous IgG-binding domains of staphylococcal protein A.

Because of the complexity arising from the large molecular size and the amino acid sequence homologies of IgG-binding domains of Staphylococcal Protein A (SpA), we have introduced, a combination of stable isotope labeling and both qualitative and quantitative investigations of the structural dependence of the NMR chemical shifts for its structure analysis. In order to enable selective isotope labeling with high efficiency, a mutated low molecular weight Protein A (LPA; MWt = 27 kDa) which consists of E, D, A, B and 13 residues of the C-domain was used in this study. Amide proton chemical shifts, measured using uniformly 15N-labeled LPA and LPA labeled selectively with 15N-alanine, show that the turn between helices 1 and 2, and its tertiary interactions with helix 3, are very similar in all domains. This contradicts previous results obtained using independent structure calculations on isolated domains. The close similarity in NH and 15N chemical shifts of alanine residues in the interdomain linker suggests that the linker maintains a similar structure both in isolated domains and in the intact protein. We show that the high-field shifted methyl signal of Ala 48 is affected by the ring-current effect arising from Phe 30, and has a very similar helical environment in all four domains. Thus, helix 3 is present in all domains, as we previously reported [Kikuchi et al., J Biochem Biophys Method, 1999:38:203-208], even though it is not observed in the crystal structure [Deisenhofer J. Biochemistry 1981;20:2361-2370].

Spectroscopic investigation of tertiary fold of staphylococcal protein A to explore its engineering application.

Staphylococcal protein A is a cell wall constituent of most strains of Staphylococcus aureus, and it is characterized by its binding affinity to some immunological classes. A mutated low molecular weight type protein A (LPA; Mwt = 27 kDa) which consists of the domains, E, D, A, B and 13 residues of the C-domain was prepared in this study. Since LPA does not possess a cell wall-bound region in contrast to wild-type protein A (WPA; Mwt = 42 kDa), we have established a methodology of large scale purification of LPA without using any extracellular expression systems such as Escherichia coli. Using this relatively abundant protein, the immobilization of the LPA with silk fibroin of Bombyx mori was performed. Thermal stability of LPA immobilized with silk fibroin is higher than that of free LPA at high temperature judging from the immunoglobulin G (IgG)-binding affinity. However, the apparent value of its affinity decreased relative to that of immobilized WPA. These results indicate that structural information is essential to explore improvement of IgG-binding affinity of immobilized LPA. Therefore, secondary structure of free LPA was detected by its characteristic helical pattern in circular dichroism (CD) in aqueous solution. In addition to this, tertiary fold of four IgG-binding domains were investigated by two-dimensional 1H-NMR spectra. Four significantly high-field shifted cross-peaks attributed to methyl signals of alanine residues suggest that all four domains pack into a three helix bundle motif in solution. These structural data and properties of IgG-binding affinity suggest that spatial arrangement of four IgG-binding domains are packed into a compact globular molecular shape. This causes a certain active site of immobilized LPA to be buried in the silk fibroin fiber.

The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase.

Solid tumours develop an acidic extracellular environment with high concentration of lactic acid, and lactic acid produced by glycolysis has been assumed to be the major cause of tumour acidity. Experiments using lactate dehydrogenase (LDH)-deficient ras-transfected Chinese hamster ovarian cells have been undertaken to address directly the hypothesis that lactic acid production is responsible for tumour acidification. The variant cells produce negligible quantities of lactic acid and consume minimal amounts of glucose compared with parental cells. Lactate-producing parental cells acidified lightly-buffered medium but variant cells did not. Tumours derived from parental and variant cells implanted into nude mice were found to have mean values of extracellular pH (pHe) of 7.03 +/- 0.03 and 7.03 +/- 0.05, respectively, both of which were significantly lower than that of normal muscle (pHe = 7.43 +/- 0.03; P < 0.001). Lactic acid concentration in variant tumours (450 +/- 90 microg g(-1) wet weight) was much lower than that in parental tumours (1880 +/- 140 microg/g(-1)) and similar to that in serum (400 +/- 35 microg/g(-1)). These data show discordance between mean levels of pHe and lactate content in tumours; the results support those of Newell et al (1993) and suggest that the production of lactic acid via glycolysis causes acidification of culture medium, but is not the only mechanism, and is probably not the major mechanism responsible for the development of an acidic environment within solid tumours.

Novel extracellular alkaline metalloendopeptidases from Vibrio sp. NUF-BPP1: purification and characterization.

We found two types of novel alkaline metalloendopeptidases (AP1 and AP2) from a marine bacterium, isolated from the intestine of a five-barred goatfish (Parupeneus trifasciatus) and identified as Vibrio sp. (NUF-BPP1). We studied the structure-function relationship of these marine bacterial proteases. The electrophoretically homogeneous proteases had a molecular mass of 48 kDa for AP1 and 36 kDa for AP2 on SDS-PAGE, and showed optimum activity at around pH 9.5-10.0 (casein as substrate). Calcium chloride (5 mM) stabilized the activities over pH 6-11, but o-phenanthroline and EDTA inhibited the activities of both AP1 and AP2. The EDTA-inactivated proteases were partly restored to activity by addition of either zinc or calcium. Sodium chloride (3.5 M) increased the activities toward Z-Gly-Leu-NH2. N-Terminal sites of hydrophobic amino acid residues (Leu, Ile, Phe, Tyr, and Trp) of the peptide substrates were cleaved by AP1 and by AP2. Autolysis of AP1 in the absence of calcium ion probably produced AP2 by releasing a fragment (molecular mass of about 12 kDa) from the C-terminal end of AP1.

A novel therapy for internal hemorrhoids: ligation of the hemorrhoidal artery with a newly devised instrument (Moricorn) in conjunction with a Doppler flowmeter.

OBJECTIVES: To assess the usefulness of hemorrhoidal artery ligation (HAL) for internal hemorrhoids with a newly devised instrument (the Moricorn). METHODS: We devised a new instrument (the Moricorn) that is used in conjunction with a Doppler flowmeter. This instrument allows for easy and safe ligation of the hemorrhoidal artery. HAL with the Moricorn was performed on 116 patients with internal hemorrhoids who had episodes of anal pain, bleeding, and prolapse. One month after treatment, the effect was evaluated on the basis of improvement of symptoms and the shrinkage of hemorrhoidal tissue. RESULTS: The treatment's effect was observed in 50 of 52 patients (96%) with pain, 50 of 64 (78%) with prolapse, and 92 of 96 (95%) with bleeding. No patient required anesthesia throughout the entire procedure. No major complications were encountered with this treatment. CONCLUSIONS: HAL with the Moricorn is a simple, safe, and effective method. However, further observations predicated on a longer follow-up, a larger number of patients, and comparisons with other conventional treatments are called for.

Antitumor activity of nigericin and 5-(N-ethyl-N-isopropyl)amiloride: an approach to therapy based on cellular acidification and the inhibition of regulation of intracellular pH.

The extracellular pH (pHe) in solid tumors is frequently lower than the pHe in normal tissues, but the intracellular pH (pHi) is regulated to physiological levels. Cell killing can be achieved in an acidic environment in tissue culture by nigericin, which acidifies cells by transporting H+ from the extracellular space into the cytoplasm; this cell killing can be enhanced when used with 5-(N-ethyl-N-isopropyl)amiloride (EIPA), a potent inhibitor of membrane-based Na+/H+ exchange, which plays a major role in the regulation of pHi (R. P. Maidorn; E. J. Cragoe; I. F. Tannock, Br. J. Cancer 67:297-303; 1993). We have therefore assessed the ability of nigericin and EIPA to kill cells in two murine solid tumors (the KHT fibrosarcoma and the EMT-6 sarcoma). Hydralazine, which reduces tumor blood flow, or glucose, which stimulates glycolysis leading to accumulation of lactate, were also administered to mice to lower pHe in the tumors. We observed only a small decrease in the surviving fractions of cells in the tumors when tolerated doses of nigericin and EIPA were given IP to tumor-bearing mice. When nigericin and EIPA were combined with administration of hydralazine, the surviving fraction of cells in both tumors was reduced by a factor of 0.01, but there were minimal effects on growth delay. Administration of glucose with nigericin and EIPA led to a smaller reduction in surviving fraction of the KHT tumor (by approximately 0.1), although glucose was more effective than hydralazine in lowering the mean tumor pHe. When KHT tumors were treated with 15 Gy X-rays followed immediately by nigericin, EIPA, and hydralazine, a reduced surviving fraction as well as an increase in tumor growth delay was observed compared to radiation alone; however, there was little evidence to suggest that these agents were selectively toxic to the cells that survived radiation. Nigericin and EIPA, with or without hydralazine, had minimal effects on normal tissues, as assessed by changes in body weight, number of leukocytes, and serum creatinine levels. We conclude that pharmacological effects to acidify cells and to prevent regulation of pHi under the acidic conditions that exist in solid tumors can lead to moderate levels of cell killing, if additional strategies are used to lower tumor pHe.

Protein characterizations and immunological properties of the low-molecular-mass protein A isolated from Staphylococcus aureus KS 1034.

The extracellular low-molecular-mass protein A isolated from Staphylococcus aureus KS 1034 was analyzed for its amino acid contents and terminal amino acid sequences. The C-terminal and the N-terminal amino acid sequences of the low-molecular-mass protein A were -Asn-Ala-Phe and Ala-Gln-His-Asp-Glu-Ala-Gln-, respectively. For immunochemical properties, the low-molecular-mass protein A was similar to protein A isolated from S. aureus Cowan I. Extracellular protease activity of KS 1034 strain was considerably lower than S. aureus C-30 isolated from chicken that produced the extracellular low-molecular-mass protein A.

Therapeutic efficacy of two-route chemotherapy using cis-diamminedichloroplatinum(II) and its antidote, sodium thiosulfate, combined with the angiotensin-II-induced hypertension method in a rat uterine tumor.

To enhance the therapeutic effect of conventional TRC using intra-arterial (i.a.) DDP plus simultaneous i.v. STS, we combined the AT-II-induced hypertension method with TRC and evaluated its efficacy for a rat uterine tumor, using the simulation of intra-arterial chemotherapy for human uterine tumors. During interruption of arterial blood flow by vascular manipulations, DDP plus AT-II were injected for 10 min through the abdominal aorta in the direction of the uterus. Then STS was administered i.v. for a further 5 min and all the arterial restrictions were released. This modified TRC using AT-II showed a much higher anti-tumor effect than that seen in conventional TRC without AT-II and was free from DDP-induced renal damage. On the other hand, severe nephrotoxicity was unavoidable in the rats given the delayed i.v. administration of STS to i.a. DDP alone. The feasibility of post-administration of STS without obvious nephrotoxicity in modified TRC was explained by transient inhibition of DDP delivery to the kidney during the AT-II-induced hypertension. The loss of body weight and the decrease in the number of leukocytes after this therapy were tolerable. Modified TRC showed a higher anti-tumor effect and a lower nephrotoxicity compared with other treatments, as follows: DDP i.a. with or without AT-II; i.v. infusion of DDP alone. Such a superior anti-tumor effect of modified TRC consists of the following 2 factors: (i) the post-administration of STS leading to the delayed neutralization of DDP at the tumor site; (ii) the selective enhancement of DDP delivery to the tumor tissue during AT-II-induced hypertension.

YS-822A, a new polyene macrolide antibiotic. II. Planar structure of YS-822A.

The planar structure of a new polyene macrolide antibiotic, YS-822A, which was isolated from the culture filtrate of a mutant strain H-8 of Streptoverticillium eurocidicum var. asterocidicus S-822, was established as I on the basis of spectroscopic evidences and by comparison spectroscopic data with nystatin A1 (II) and amphotericin A (III), representative polyene macrolide antibiotics. Molecular formula of YS-822A was established as C37H59NO14 (MW 741) by elemental analysis, NMR, and FAB mass spectra. The UV spectrum of YS-822A was very similar to that of nystatin A1, suggesting that YS-822A also has a conjugated all-trans-tetraene moiety. 1H and 13C NMR spectra of YS-822A showed a number of broad and overlapped signals, but the 1H-1H and 13C-1H COSY spectra implied the existence of a mycosamine moiety and several other partial structures. The connectivity of these partial structures was established by extensive 2D NMR experiments, including homonuclear Hartmann-Hahn and heteronuclear multiple-bond connectivity measurements, which led to the determination of the gross planar structure of YS-822A as I.

Increased therapeutic efficacy of intra-arterial carboquone chemotherapy on a limb tumor in rats, by using an acidic vehicle adjusted with lactate.

We previously reported that the cytotoxicity of carboquone (CQ) was potentiated in vitro and in vivo under acidic conditions. In this study, an acidic vehicle adjusted with lactate at various low pHs was used for CQ intra-arterial (i.a.) injection, in order to enhance the antitumor effects of i.a. CQ chemotherapy. Treatments were evaluated in Wistar/KA rats bearing a limb tumor 5 days after the inoculation of 3 x 10(6) syngeneic RBT-1 tumor cells into the hind limb. In chemotherapy experiments using an intrafemoral injection of CQ at 1.5 mg/kg in phosphate-buffered saline (PBS, pH 7.4) or in an acidic vehicle at pH 5.0 or 6.0, the antitumor effects seen in rats given CQ in acidic vehicles, evaluated by tumor weight 14 days after treatment, were significantly greater than that seen in rats given CQ in PBS. There were no significant differences either in changes of body weight or in the number of leukocytes after treatment between the groups given CQ in PBS and in an acidic vehicle at pH 6.0. Although in the group given CQ at 2.0 mg/kg in PBS, the antitumor effect was the same as that observed in rats given CQ at 1.5 mg/kg in an acidic vehicle at pH 6.0, the side effects observed in the former group were much severer than in the latter group. These data suggest that the antitumor effect of i.a. CQ chemotherapy can be potentiated by using an acidic vehicle.

YS-822A, a new polyene macrolide antibiotic. I. Production, isolation, characterization and biological properties.

A new polyene macrolide antibiotic, YS-822A was isolated from the culture filtrate of a mutant strain H-8 of Streptoverticillium eurocidicum var. asterocidicus S-822. Whereas the original S-822 strain produced not only YS-822 substances but also teleocidin as by-product which is well-known as a strong carcinogenic promoter, the mutagenized H-8 strain produced the antibiotic with only a trace amount of teleocidin. Chemical and biological characterizations of the antibiotic revealed that YS-822A (molecular formula: C37H59NO14) is a new polyene macrolide with a wide antifungal spectrum and a low acute toxicity.

Systemic chemotherapy in tumor-bearing rats using high-dose cis-diamminedichloroplatinum(II) with low nephrotoxicity in combination with angiotensin II and sodium thiosulfate.

Systemic chemotherapy using high-dose DDP and its antidote, STS, was combined with the AT-II-induced hypertension method and evaluated for efficacy against s.c. tumors in rats. After i.v. infusion of DDP plus AT-II for 5 min, STS was administered i.v. over a further 5 min. The rats treated with this combination chemotherapy showed normal levels of BUN and serum creatinine 4 days after the treatment, although most rats given i.v. STS after DDP without AT-II showed severe nephrotoxicity. The absence of obvious nephrotoxicity in AT-II-combined chemotherapy using i.v. DDP plus post-administered STS can be explained by a transient inhibition of DDP-delivery to the kidney during the AT-II-induced hypertension. The anti-tumor effect of this modified therapy, evaluated by inhibition of tumor growth, was superior to other treatments, as follows: concomitant i.v. administrations of DDP and STS; i.v. DDP, with or without AT-II. The improvement in anti-tumor effect of this combination therapy is explained by the delayed neutralization of active DDP by STS at the tumor site and the selective enhancement of DDP delivery to the tumor tissue, as produced by AT-II. Thus, systemic chemotherapy using high-dose DDP induced no obvious nephrotoxicity and improved the anti-cancer effect in the case of concomitant administration of DDP plus AT-II and the time-delayed injection of STS.

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

To improve the therapeutic effects of conventional "two-route chemotherapy" (TRC) comprising cis-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 10(6) 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.

Efficacy of two-route chemotherapy using cis-diamminedichloroplatinum(II) and its antidote, sodium thiosulfate, in combination with angiotensin II for rat liver tumor.

To improve the therapeutic effects of conventional TRC using i.a. CDDP plus simultaneous i.v. STS in a rat liver tumor, we made use of the AT-II-induced hypertension method, in combination with TRC. The decrease in tumor area (-15%), measured 8 days after the TRC using CDDP 12 mg/kg i.a. plus i.v. post-administration (5 min later) of STS 1,264 mg/kg, was much greater than that (+ 13%) seen in the conventional TRC, but BUN level was elevated (44.9 mg/dl). AT-II (15 micrograms/kg) administered i.a. simultaneously with CDDP normalized the BUN level (20.3 mg/dl) and further decreased (-15% to -31%) the tumor area (modified TRC). The modified TRC also exhibited a higher anti-tumor effect than did CDDP 3 mg/kg with AT-II i.a. (5%) at a similar BUN level (22.2 mg/dl). Loss of body weight, decrease in WBC count and changes in serum transaminases of rats treated with the modified TRC were tolerable. The improved therapeutic effect of the modified TRC was explained as follows: during AT-II-induced hypertension, (I) CDDP delivery to the tumor was increased by 150% and (2) CDDP delivery to the kidney was decreased by 35%. The latter effect of AT-II made feasible the post-administration of STS to CDDP.

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.

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

"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 micrograms/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.