Inhibitory effects of subcutaneous dexamethasone treatment on rat pulmonary toxicity of KW-2149, a new mitomycin C analogue

An experimental model for pulmonary toxicity of KW-2149, a new mitomycin C analogue, was established and the inhibitory effects of dexamethasone (DM) were investigated. KW-2149 was given to male rats 3 or 5 times at weekly intervals by intravenous injection of 3.28 or 8.2 mg/kg. As a suitable model for pulmonary toxicity, the dose of 3.28 mg/kg per week for 3 weeks was selected, this causing exudative pleural effusion in all animals but no deaths. For preventing this toxicity, DM was injected subcutaneously 3 times every week at 0.5, 1.0, 2.5 or 5.0 mg/kg. The 0.5 mg/kg dose was sufficient to completely prevent development of pleural effusions. Combined DM treatment may be an effective chemotherapy for KW-2149 induced pulmonary toxicity. Received: 16 November 1999 / Accepted: 18 January 2000     

Inhibitory effects of repeated intravenous injections of dexamethasone on pulmonary toxicity of a new mitomycin C analogue, KW-2149, in a novel rat model

An animal model for testing pulmonary toxicity of KW-2149, a new mitomycin C analogue, was developed (by intravenously injecting 3.28 mg/kg of the drug into male SD rats 3 times at weekly intervals), and exhibits pleural effusion from 1 week after the last injection. In this animal model, repeated intravenous injections of dexamethasone (DM), following any of three different schedules examined, were more or less effective of reducing the amount of effusion. The optimal results were obtained with 4 administrations a week (i.e. twice before and twice after KW-2149 treatment). The results of the present experiment suggest possible clinical application of DM in protecting patients from pulmonary toxicity of KW-2149.     

Antitumor effect of a newly synthesized celecoxib derivative encapsulated in liposome

A new cyclooxygenase-2 inhibitor (code: PCX-3) was synthesized as a sodium salt form of celecoxib, a non-steroidal anti-inflammatory drug (NSAID), and tested for its anticancer activity using human colon adenocarcinoma cells (HT-29) in vitro. Anti-proliferative effect of HT-29 cells by PCX-3 in DPPC/Chol liposomes was more effective than the free PCX-3 by 2-folds (IC₃₀ = 125 μM vs. 227.5 μM). The same liposomal formulation of PCX-3 also showed a 2-fold increased effect than the free one both in DNA fragmentation and caspase activity of HT-29 cells at 19-743 μM and 37–371 μM ranges, respectively, suggesting apoptosis-based anti-proliferative effect. Down regulation of prostaglandin E₂ level of HT-29 cells by the treatment of liposomal PCX-3 was more profound than its free form at 0.001–0.002 μM range. These data suggest that the liposomal formulation of this newly synthesized PCX-3 could be re-visited as a new anticancer or chemo-preventive agent in the future.     

Insulin resistance-reducing effect of a new thiazolidinedione derivative, pioglitazone]

Takeda has a relatively long history in diabetes research. Pioglitazone, a thiazolidinedione derivative, was developed from our basic research on diabetic animal models in the 1960s and our chemical research on lipid-lowering agents in the 1970s. Pioglitazone reduced plasma glucose, triglyceride and insulin levels in obese-diabetic animal models with insulin resistance in liver and/or peripheral tissues, but did not decrease normoglycemia in normal rats and aged dogs or hyperglycemia in insulin-deficient streptozocin-induced diabetic rats and impaired-insulin-secretory Goto-Kakizaki rats. The ED50 of plasma glucose-lowering action was 0.5 mg/kg/day in Wistar fatty rats. These findings clearly indicate that pioglitazone works in animals with insulin resistance and has a quite different mechanism from sulfonylureas and insulin itself. Although the exact mechanism of pioglitazone still remains obscure, pioglitazone normalized abnormalities in the cellular signal transduction of insulin. These effects seem to be due to the inhibitory action of pioglitazone on TNF-alpha production, which is one of the factors responsible for insulin resistance. Pioglitazone is a potent agonist for the peroxisome proliferator-activated receptor, (PPAR)-gamma, that is related to differentiation of adipocytes, and the relationship between TNF-alpha production and PPAR-gamma has been reported. Therefore, the agonistic activity of pioglitazone on PPAR-gamma may be involved in the mechanism of reduction of insulin resistance. The clinical data clearly demonstrated that pioglitazone, at clinical doses of 15-45 mg/day, decreased plasma glucose, HbA1c and triglyceride, increased plasma HDL-cholesterol, but did not alter total cholesterol and LDL-cholesterol levels. These findings suggest that pioglitazone has a benefit for prevention of cardiovascular diseases in addition to diabetic complications.     

丝裂霉素C壳聚糖纳米粒对H22荷瘤小鼠的肿瘤抑制作用

目的研究丝裂霉素C壳聚糖纳米粒（MMC—CS-NPs）对H22荷瘤小鼠的肿瘤抑制作用。方法采用小鼠H22肝癌细胞实体瘤模型进行体内抑瘤实验,观察荷瘤动物的生长情况,并测定肿瘤生长抑制率;肿瘤组织病理学切片行HE染色以进行形态学观察。结果MMC-CS-NPs对小鼠的H22实体瘤生长具有明显的抑制作用,低、中、高剂量组的抑瘤率分别为52．23％、66．93％、80．91％,与对照组相比有统计学意义（P〈0．05）。病理组织学观察显示,各剂量组对肿瘤组织都有不同程度的破坏,肿瘤细胞大量变性坏死。结论MMC-CS-NPs具有较强的体内抗肿瘤作用,与丝裂霉素针剂相比其抑瘤率更高,且与剂量有关,并对肿瘤生长的抑制更为持久。     

Antitumor effects of a podophyllotoxin derivative, VP 16-213

Single and combination chemotherapies of VP 16-213, a new antitumor agent were evaluated for its antitumor effect against several murine tumors. Dose-dependent antitumor effects were observed when VP 16-213 was administered via any of the three routes, i.p., i.v. and orally, on days 1 and 5 after i.p. or s.c. inoculation of Ehrlich carcinoma and sarcoma 180. The drug also proved effective against i.v. inoculated EL-LP-12 (subline of Ehrlich carcinoma), i.p. or s.c. inoculated P388 and B16 melanoma, i.p. inoculated colon 26, and s.c. inoculated colon 38 and Lewis lung carcinoma. However, oral administration of the drug was not effective against B16 melanoma, colon 26 and Lewis lung carcinoma despite the fact that the doses employed for this route was higher than those employed for i.v. and i.p. routes. The optimum dosing schedule was also investigated with oral administration of the drug against s.c. inoculated Ehrlich carcinoma. A single dose (day 1) or two doses (days 1 and 5) were more effective than three doses (days 1, 3 and 5) or five consecutive daily doses. VP 16-213 showed additive and more than additive effects in combination with the antitumor agents, cyclophosphamide, BCNU, mitomycin C or cisplatin against s.c. inoculated Ehrlich carcinoma and i.v. inoculated EL-LP-12.     

Antitumor and antiangiogenic effects of GA-13315, a gibberellin derivative

This study showed that 13-chlorine-3,15-dioxy-gibberellic acid methyl ester (GA-13315), a gibberellin derivative, possessed high antitumor and antiangiogenic activity in vitro and in vivo. Cytotoxicity assays showed that GA-13315 was a potential and efficient antitumor compound, with inhibitory concentration 50 (IC₅₀) values ranging from 0.13 to 30.28 μg/ml in 12 human tumor cell lines, and it showed moderate toxicity to peripheral blood mononuclear cells with an IC₅₀ value of 14.2 μg/ml. Administration of 0.5 or 2.5 mg/kg GA-13315 for 23 days significantly inhibited tumor growth of human non-small cell lung tumor (A549) xenografts, with relative growth rates ranging from 29.91% to 35.05%. Acute toxicity was determined in ICR mice, and the lethal dose 50 (LD₅₀) was 4.19 g/kg after intragastric administration. The high antitumor potency of GA-13315 occurred in parallel with its antiangiogenic activity. In vitro, GA-13315 inhibited recombinant human epithelial growth factor-induced chemotactic motility and capillary-like tube formation of primary cultured human endothelial cells. Furthermore, GA-13315 decreased the factor VIII⁺ microvessel density and vascular endothelial growth factor expression in A549 tumors, indicating its antiangiogenic efficacy in vivo. These results indicate that the antiangiogenic activity of GA-13315 contributes to its anticancer properties. Further studies are needed to investigate the use of GA-13315 as an anticancer drug.     

Antitumor activity of KF22678, a novel thioester derivative of leinamycin

KF22678, a novel thioester derivative of leinamycin with the 1-oxo-1,2-dithiolane-3-one moiety, was examined for anti-tumor activity, toxicity in mice and activation mechanism. KF22678 showed a broad antitumor spectrum against human carcinoma xenografts (lung, colon, ovary and prostate). The efficacy of KF22678 was significantly higher than that of cisplatin. KF22678 exhibited low cross-resistance against various drug-resistant cell lines of MDR1 or MRP overexpressing human tumors, and, in addition, exhibited more potent antitumor activity in vivo than ADM against A2780/ADM and KB/MRP xenograft. DL-Buthionine sulfoximine (BSO) pretreatment significantly reduced intracellular glutathione (GSH) level in human lung carcinoma A549 cells, leading to decrease in the cytotoxicity of KF22678, whereas the cytotoxicity of melphalan was augmented by BSO pretreatment. DNA single-strand breaks (SSB) were observed in A549 cells treated with KF22678 and bleomycin. DNA SSB induced by KF22678 was greatly reduced in the presence of BSO in the cells, whereas DNA SSB induced by bleomycin was not. In addition, the antitumor activity of KF22678 against BSO-pretreated human lung carcinoma PC-9 tumor was significantly decreased. These results suggest that the activation of KF22678 by intracellular GSH might be important for DNA SSB and antitumor activity in vitro and in vivo.     

Antitumor effects of KITC, a new resveratrol derivative, in AsPC-1 and BxPC-3 human pancreatic carcinoma cells

Pancreatic cancer is a very aggressive malignant disease due to lack of early diagnosis and chemotherapeutic resistance of the tumor cells. There is distinct evidence that food derived polyphenols possess chemopreventive effects in the development of several cancers including pancreatic carcinoma. Resveratrol is one of those phenolic compounds found in grape skins and other fruits with known anticancer activity. Various polymethoxylated resveratrol derivatives showed stronger antiproliferative effects than resveratrol in tumor cell lines. The aim of our study was to evaluate the cytotoxic and biochemical effects of a newly synthesized polymethoxylated resveratrol analogue, N-hydroxy-N'-(3,4,5-trimethoxphenyl)-3,4,5-trimethoxy-benzamidine (KITC) in two human pancreatic cancer cell lines. The human pancreatic cancer cell lines, AsPC-1 and BxPC-3 were used to test the potential inhibitory effect of the resveratrol derivative on cell proliferation and the underlying mechanisms of this effect. After 7 days of incubation, KITC inhibited the growth of AsPC-1 and BxPC-3 cells with IC(50) values of 9.6 and 8.7 microM, respectively. KITC (40 microM) arrested cells in the G0/G1 phase and depleted cells in the S phase of the cell cycle (-105% and -35% of control, respectively). KITC induced dose-dependent apoptosis in both pancreatic cancer cell lines and was found to significantly reduce the in situ activity of ribonucleotide reductase, the key enzyme of DNA synthesis. Employing growth inhibition assays, KITC acted synergistically with gemcitabine in both cell lines. In summary, we found that KITC exerted considerable antitumor activity against human pancreatic cancer cells and could be a promising candidate for further investigations to establish a new chemotherapeutic regimen.     

Antitumor activity of a new antibiotic, kazusamycin

The antitumor activity of a new antibiotic, kazusamycin, against various murine tumors was studied by various treatment schedules. Single, intermittent, and successive injections of the antibiotic were almost equally effective against Ehrlich carcinoma, IMC carcinoma and sarcoma 180 tumor, but successive injections showed more efficacy than the other schedules against Meth A fibrosarcoma and Lewis lung carcinoma. Interestingly, there was no clear dose response for the efficacy of kazusamycin on murine tumors. When HeLa cells were exposed to kazusamycin for 72 hours in vitro, the IC50 value was about 1 ng/ml, however the cytotoxicity of the antibiotic depended on the incubation time.     

Gastric antisecretory and anti-ulcer effect of ME3407, a new benzimidazole derivative, in rats

The effects of a new benzimidazole derivative, ME3407 (n-butyl-2-(thiazolo-[5,4-b]pyrid-2-yl) sulfinylacetate, CAS 133903-90-9), on gastric acid secretion and gastric and duodenal ulcers in rats were examined. ME3407, given orally, inhibited dose-dependently (0.3-30 mg/kg) the incidence of gastric lesions such as Shay ulcers, and water-immersion stress-, acetylsalicylic acid (ASA)- and histamine-induced erosions. In addition, ME3407 showed marked therapeutic effect on HCl- and ASA-induced lesions. In the lumen-perfused rats, oral administration of ME3407 inhibited dose-dependently (1-100 mg/kg) gastric acid secretion induced by histamine and tetragastrin with ED50 values of 3.02 and 3.37 mg/kg, respectively. Oral administration of ME3407 at a dose of 30 mg/kg also inhibited the elevation of serum gastrin level. The development of duodenal ulcers caused by mepirizole and systeamine was also potently inhibited by ME3407 at an oral dose of 0.1-30 mg/kg. However, when given at 30 mg/kg intraduodenally, subcutaneously or intravenously, ME3407 did not inhibit these acutely induced gastric elosion and acid output. ME3407 was not detected in the serum upon oral administration. These results indicated that ME3407 was active only by oral administration, and exerts direct action on the ulcers and acid secretion from the gastric membrane.     

Antihypertensive and vasodilator effect of A-80b, a new pyridazino indole derivative.

The hypotensive and antihypertensive activities of a A-80b, a newly synthesized pyridazino[4,5-b]indole derivate were investigated in anaesthetized rats. In vitro studies were also done to examine the possible mechanism of its vasodilator action. A 80b (3-15 mg/kg i.p.) showed potent and long-lasting antihypertensive activity in spontaneous hypertensive rats. In normotensive rats, A-80b (7.5-30 mg/kg i.p.) also lowered blood pressure but less than in hypertensive rats. The decrease in diastolic pressure was greater than the decrease in systolic pressure and cardiac frequency was not modified significantly. Contractile responses induced in isolated rat thoracic aorta by K+ and noradrenaline were inhibited by A-80b. In K(+)-depolarized rat aorta, A-80b showed dose-dependent inhibition of the Ca(2+)-induced contraction. Also, A-80b inhibited spontaneous contractions of rat portal vein. The vasodilator action seemed to be endothelium-independent. These results suggest that A-80b is a new chemical entity which exerts a hypotensive and antihypertensive effect, possibly attributable to vasodilator activity via interference with Ca2+ influx and probably Ca2+ mobilization from intracellular stores.     

Antiviral activity and inhibition of topoisomerase by ofloxacin, a new quinolone derivative

The antiviral activity of ofloxacin, a new quinolone derivative, against vaccinia virus (VV), herpes simplex virus (HSV) and influenza virus (InfV) was evaluated in both in vitro and in vivo experiments. As a result, ofloxacin showed inhibitory activity against VV in cultured mammalian cells, and prevented formation of pox tail lesions in VV-infected mice. However, it was less effective against HSV and InfV than VV. The antiviral activity of ofloxacin assessed by VV tail-lesion test was strongest when administered to mice through the oral route daily for five consecutive days post-infection. Nalidixic acid and novobiocin, well-known gyrase inhibitors, showed only weak antiviral activity in both in vitro and in vivo tests against VV. It was also demonstrated that ofloxacin inhibited virus-specific DNA and RNA syntheses. It was more inhibitory to VV topoisomerase than cellular topoisomerases. Thus, ofloxacin has selectivity for VV.     

Stimulation of sympathetic cardiovascular centres by RA 642, a new pyrimido-pyrimidine derivative

Summary RA 642, 2,2-[4,8-bis(diethylamino)-pyrimido[5,4-d] pyrimidine-2,6-diyl)di-(2-methoxyethyl)-imino]diethanol, has formerly been described to be hypertensive when administered systemically. In the present experiments injection of 50 g/kg RA 642 into the vertebral artery (i.a. vert.) of the cat exerted hypertension, while the same dose given intravenously (i.v.) elicited no effect. Since the drug was still effective in cats of which the brain was removed rostrad of the myelencephalon but not in spinal animals, its site of action was concluded to be in cardiovascular centres of the medulla oblongata. An i.a. vert. injection increased total peripheral resistance of the vasculature. The electrical discharge rate in preganglionic cervical sympathetic nerve fibres increased in parallel to the arterial blood pressure following the i.v. injection of 1 mg/kg of the substance. 1 mg/kg RA 642 i.v. decreased the reflex bradycardia elicited by the i.v. injection of angiotensin in dogs pretreated with a -adrenoceptor blocking drug to study the vagal effector reactions of the baroreceptor reflex, and treated with clonidine to facilitate the reflex. Thus, RA 642 increased sympathetic and, following clonidine treatment, decreased vagal reflex activity.RA 642 stimulated the respiration by a central action. The drug had no convulsant action.