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Biomedical subjects

S Hiraki

Publications and source records attributed to S Hiraki.

At least 37 records · Page 2Linked to original sources
PubMed1997

Growth inhibitory effects of antifolates against an adriamycin-resistant human small cell lung cancer cell line.

We have established an Adriamycin (ADM)-resistant small cell lung cancer (SCLC) cell line, SBC-3/ADM 100, which shows multifactorial mechanisms of resistance to ADM, such as over-expression of P-glycoprotein, an enhanced detoxifying system and a decrease in topoisomerase II activity. In the present study, we confirmed that SBC-3/ADM 100 showed collateral sensitivity to methotrexate and TNP-351, a new antifolate, though this cell line showed a typical multidrug resistance (MDR) pattern. We also demonstrated a faster uptake and higher accumulation (1.3-fold) of TNP-351 in the SBC-3/ADM 100 cells than those in the parent SBC-3 cells. These results explain one of the mechanisms for collateral sensitivity in the resistant cells. Furthermore, this cell line was found to have no cross-resistance to edatrexate and minimal cross-resistance to trimetrexate, 254-S (cisplatin analog), 5-fluorouacil and 4-hydroperoxyifosfamide. These drugs will have clinical importance in patients with SCLC who were previously treated with an ADM-containing regimen. Thus, antifolates, especially TNP-351 and edatrexate, can be expected to eradicate residual multidrug resistant SCLC cells selected by ADM.

Animals↗
PubMed1997

[A patient with bronchial asthma and mucoid impaction who presented with a high concentration of carcinoembryonic antigen in serum].

We encountered a patient with bronchial asthma and mucoid impaction who presented with a high concentration of carcinoembryonic antigen (CEA) in serum. The patient was a 46-year-old woman. One year after resection of a uterine myoma and an ovarian cyst, examination of serum revealed a high concentration of CEA (24.1 ng/ml). Further examination revealed no evidence of malignant disease, but an abnormal shadow was seen on a chest X-ray film, and was thought to be compatible with mucoid impaction. Fiberoptic bronchoscopy revealed mucoid impaction in the right lower-lobe bronchus. The concentration of CEA in bronchoalveolar lavage fluid was also high (6100 ng/ml). Lavage was done five times and the impaction was removed completely. The concentrations of CEA in serum and in bronchoalveolar lavage fluid decreased to 3.4 ng/ml and 621.9 ng/ml, respectively.

Adult↗
PubMed1996

Decreased aqueous-flare reaction to repeated applications of prostaglandin E2 to the cornea in pigmented rabbits.

To evaluate the effect of single or repeated topical applications of prostaglandin E2 (PGE2) to the cornea on the blood-aqueous barrier, we have measured the extent of flare in the anterior chamber of rabbit eyes at various time intervals. PGE2 was applied to the cornea for 4 min with the use of a glass cylinder in pigmented rabbits. Aqueous flare was measured by a laser flare cell meter. The flare intensity following the second application of 25 or 50 micrograms/ml of PGE2 was smaller than that following the first application. When 50 micrograms/ml of PGE2 was applied every day for 6 days, the flare intensity decreased significantly day by day. After consecutive applications of 10 micrograms/ml of PGE2 at hourly intervals, flare intensity increased up to 3 h, remained elevated from 3 to 5 h, and decreased thereafter. Repeated applications of 10 micrograms/ml of PGE2, every hour for 14 h every Monday, significantly decreased flare intensity week by week. Weekly applications of 50 micrograms/ml of PGE2 did not change flare intensity. This study indicates that the extent of the breakdown of the blood-aqueous barrier in the rabbit eye, as measured by the development of flare in the anterior chamber, is reduced with repeated PGE2 application.

Administration, Topical↗
PubMed1996

Effects of a nitric oxide synthase inhibitor on prostaglandin-induced aqueous flare elevation in pigmented rabbits.

To evaluate the possible role of nitric oxide in the pathogenesis of exogenous prostaglandin (PG) induced aqueous flare elevation, we examined the effect of NG-nitro-L-arginine methyl ester (L-NAME), an L-arginine analogue acting as a specific inhibitor of nitric oxide synthase, on the elevation of aqueous flare in pigmented rabbits. L-NAME was injected into the ear vein of the animals. PGE1, PGE2, and PGF2 alpha were administered topically to the cornea using a glass cylinder. Aqueous flare was measured using a laser flare cell meter. PGE1, PGE2, and PGF2 alpha increased the aqueous flare dose dependently (5-100 micrograms/ml). L-NAME inhibited PGE1-, PGE2-, or PGF2 alpha-induced aqueous flare elevation. L-NAME, injected 30-90 min before PG application, inhibited the aqueous flare elevation maximally. We believe that nitric oxide may be involved in the pathogenesis of PG-induced aqueous flare elevation in rabbits.

Animals↗
PubMed1996

[Effects of intra-hepatic arterial injection of mitoxantrone for hepatocellular carcinoma].

Twenty patients with unresectable hepatoma, recurrent hepatoma or metastatic liver cancer were treated by intra-hepatic arterial injection of mitoxantrone, and its effectiveness and side effects were studied. In 35.5% of the patients, complete or partial responses were seen. The survival intervals after the beginning of therapy were from one to 21 months (mean, 9.4 months) and one-year survival ratio was 56.3%. Red blood cell, leukocyte, and platelet counts diminished significantly one week later after administration of mitoxantrone compared with the pre-administration levels. Severe hepatic dysfunction has not been experienced.

Adult↗
PubMed1995

Intracameral ascorbic acid, glutathione and protein levels in albino and pigmented rabbits.

We performed a comparative investigation into differences between albino and pigmented rabbits in respect of intracameral concentrations of ascorbic acid, glutathione and total protein with high-performance liquid chromatography. The intracameral concentrations of reduced ascorbic acid, total ascorbic acid, reduced glutathione, total glutathione and protein in albino rabbits were similar (p > 0.05) to those in pigmented rabbits.

Animals↗
PubMed1995

[Pharmacokinetics of subconjunctivally injected drugs in the anterior segment of rabbit eyes].

We injected 12.5, 25, 50 and 100 microliters portions of a combined solution of 2.5% sodium fluorescein (FL), 2.5% cefmenoxim hemihydrochloride (CMX), and 0. 25% chloramphenicol (CP) subconjunctivally into rabbit eyes by various methods. Drug levels were monitored in the tears and aqueous humor and measured via high performance liquid chromatography. In the tear fluid, the concentrations of CP decreased more rapidly with time than FL and CMX. The drugs penetrated the rabbit's eyes better when injected subconjunctivally than when administered by sub-Tenon's injection. After subconjunctival injection through the eyelid, the drug concentration in the tears decreased with time in almost the same way as for injection through the conjunctival membrane. There was little difference between the presence and absence of a puncture hole in the conjunctiva. When the whole cornea was sealed with cyanoacrylate glue to block transcorneal absorption, the FL concentration in the aqueous humor was 30% of that in the control and the CP concentration was less than 10% of that in the control. About 70% of FL penetrating the eyes was derived from the transcorneal route but most of the CP was derived from the transcorneal route. FL in 1% or 0. 25% sodium hyarulonate (HA) and saline was injected subconjunctivally, and the concentrations of FL in the cornea and vitreous humor were measured. FL in 0.25% HA penetrated rabbit eyes better than that in 1% HA. These findings suggest that by dissolving the drug in an adequate concentration of HA solution, better penetration of drugs into the eye can be obtained.

Animals↗
PubMed1994

[The effects of transcorneal administration of prostaglandin E2 on rabbit eyes].

The pharmacologic effects of prostaglandin E2 (PGE2) on the anterior ocular segment were investigated. PGE2 was administered with a glass cylinder attached to the cornea in concentrations ranging from 0.05 to 500 micrograms/ml. The intraocular inflammatory reaction was assessed according to the changes in the anterior chamber flare, ocular tension, and components of the aqueous humor. We also performed experiments designed to inhibit the reactions induced by PGE2 using anti-inflammatory agents. The PGE2 elicited a single peak reaction in the anterior chamber flare, which recovered after several hours, and a transient elevation in the ocular tension in the early stage after PGE2 administration. Quantitative analysis of these two reactions revealed that both were dependent on the dose of PGE2 administered. The concentrations of ascorbic acid and glutathione, particularly that of the reduced form of the latter, were transiently reduced in the aqueous humor. The anterior chamber flares were suppressed by agents that inhibit arachdonic acid metabolism. These findings suggest that the metabolism of arachdonic acid becomes newly activated as a result of stimulation by PGE2 of extrinsic origin.

Animals↗
PubMed1994

[The effects of calcium antagonists on prostaglandin E2 reaction in rabbit eyes].

We determined the effects of calcium antagonists (CAs) on prostaglandin E2 (PGE2) induced responses in the anterior ocular segment. PGE2 was administered to pigmented rabbit eyes with a glass cylinder attached to the corneal surface. CAs (nicardipine, verapamil, diltiazem: 125-1,000 micrograms/kg) were injected intravenously either once (30 min. before or at the same time as the PGE2 administration), or twice (at the same time as the PGE2 administration and 30 min. after). We evaluated the aqueous flare (AF) for 6 hours using a laser flare cell meter and intraocular pressure (IOP). A single peak rise of AF was observed about 1 hour after the PGE2 administration and a transient elevation of IOP 15-30 min. after. Intravenously injected CAs reduced these responses. Nicardipine (500-1,000 micrograms/kg) in particular significantly suppressed both the rise of AF and the IOP elevation. These results suggest that CAs suppress ocular inflammatory responses induced by PGE2 effectively.

Animals↗
PubMed1994

[The effects of various doses of lipopolysaccharide on endotoxin-induced uveitis in rats].

We induced intraocular inflammation by foot pad injection of lipopolysaccharide (LPS) in rats to investigate the inflammatory effects of the various doses of the LPS and the anti-inflammatory effects of prostaglandin (PG) synthetase inhibitor. The aqueous protein concentration curve showed two peaks, an early one at 3 hours and another at 24 hours after the injection, at doses higher than 12.5 micrograms per rat. The PG synthetase inhibitor reduced the aqueous protein concentration by 30 to 60% at both of the two peaks. These results suggest the involvement of PG in the mechanism of the endotoxin-induced uveitis.

Animals↗
PubMed1993

Pilot study of cyclophosphamide-doxorubicin-vincristine-cisplatin-etoposide hybrid chemotherapy in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is highly sensitive to chemotherapy. Despite the introduction of intensive combination chemotherapy, long-term disease-free survivors are still rare. The emergence of drug-resistant tumor cells during chemotherapy is presumed to be the major cause of poor outcome. METHODS: A pilot Phase II study of hybrid chemotherapy for patients with SCLC was conducted between October 1986 and March 1988. Dose and schedule for each drug in the regimen were as follows: cyclophosphamide, 700 mg/m2 intravenously (IV), day 1; doxorubicin, 30 mg/m2 IV, day 1; vincristine, 1.4 mg/m2 IV, day 1; cisplatin, 60 mg/m2 IV, day 8; and etoposide, 100 mg/m2 IV, days 8 and 9. Courses were repeated every 4 weeks for up to six cycles. Patients with limited disease (LD) received chest irradiation of 5000 cGy when a maximal response was achieved. Only patients with LD who achieved a complete response (CR) received prophylactic cranial irradiation of 3000 cGy. RESULTS: Thirty-six patients were enrolled and fully evaluated for tumor response and toxicity. All 20 patients with LD responded to the regimen, and 14 (70%) of those achieved a CR. Of 16 patients with extensive disease (ED), 7 CR and 7 partial responses were noted, indicating an overall response rate of 88%. The median survival time was 23.6 months for patients with LD and 12.6 months for those with ED. Myelosuppression was the major toxicity, but it was generally well tolerated. CONCLUSIONS: These results indicate that the hybrid regimen is a highly active one for the treatment of patients with SCLC and warrants additional clinical trials.

Adult↗
PubMed1993

Comparative study of prophylactic cranial irradiation in patients with small cell lung cancer achieving a complete response: a long-term follow-up result.

Between 1981 and 1986, a total of 46 patients with small cell lung cancer (SCLC) achieving a complete response by chemotherapy with or without chest irradiation were randomized either to receive prophylactic cranial irradiation (PCI) or not. With a median follow-up time of 8.5 years for both groups, only five of 23 patients (22%) in the PCI group developed brain relapse, while 12 out of 23 (52%) in the no PCI group did so (P < 0.05). The frequency of patients developing a sole brain relapse during their whole clinical course was 4% for the PCI group and 17% for the no PCI group, however, the difference was not statistically significant. Patient survival was better for the PCI group (median survival time of 21 months, and 5-year survival rate of 22%) as compared with the no PCI group (median survival time of 15 months, and 5-year survival rate of 13%), showing a marginal significance (P = 0.097). Late neurologic toxicity was infrequent; only one developed a mild deterioration among seven long-term disease-free survivors in the PCI group. These results appear to warrant further clinical trials to clarify the utility of PCI in patients with SCLC achieving a complete response.

Adult↗
PubMed1993

Antitumor activity of platinum analogs against human lung cancer cell lines and tumor specimens.

Antitumor activities of five platinum analogs, including cisplatin, carboplatin, 254-S, DWA2114R, and NK121, were compared using five human lung cancer cell lines and 19 tumor specimens obtained from lung cancer patients. The antitumor activity was evaluated by determining the ratio of the maximum tolerated dose of each drug to the 70% tumor growth inhibitory concentration in a colony assay. Cisplatin was the most potent agent, followed by 254-S and carboplatin. DWA2114R and NK121 were less potent than cisplatin and 254-S. Cross-resistance to adriamycin was also investigated using an adriamycin-resistant small cell lung cancer subline, SBC -3/ADM30. SBC-3/ADM30 was 1.7- to 4.0-fold more resistant to cisplatin, carboplatin, NK121, and DWA2114R, than was the parent line, SBC-3, and the subline was 2.0-fold more sensitive to 254-S. Using SBC-3, in vitro combination effects of etoposide and cisplatin, carboplatin, or 254-S were evaluated by the median-effect principle. Synergism was noted when cisplatin and etoposide were combined at a fixed molar ratio of 1:1. Combination of carboplatin and etoposide showed an additive effect. The combination of 254-S and etoposide was antagonistic at low concentrations, but was markedly synergistic at higher concentrations. These data suggested the efficacy of 254-S in the treatment of lung cancer.

Antineoplastic Agents↗
PubMed1993

Immunohistochemical detection of P-glycoprotein and carcinoembryonic antigen in small cell lung cancer: with reference to predictability of response to chemotherapy.

In an attempt to elucidate the tumor properties relating to responsiveness to chemotherapy, we examined immunohistochemically the expression of P-glycoprotein (P-gp) and carcinoembryonic antigen (CEA) in small cell lung cancer (SCLC) tumors. Tumor specimens from 33 patients were obtained at the time of diagnosis and relapse. Four patients expressed P-gp in their initial tumors, and 7 others did in recurrent tumors. The overall response rate to chemotherapy of the initial tumors was 75% for P-gp-positive initial tumors and 86% for P-gp-negative tumors, whereas the disease-free and overall survival times were significantly shorter in the former than the latter. Three patients showed CEA in their initial tumors, and 5 others did in recurrent tumors. The patients with CEA-positive initial tumors tended to relapse earlier than those with CEA-negative tumors. In addition, recurrent tumors expressing CEA were resistant to salvage chemotherapy. A clear correlation between CEA expression by tumors and the CEA level in the serum was observed at diagnosis as well as at relapse. These findings indicate that P-gp and/or CEA expression by a tumor and elevated CEA level in the serum may predict refractoriness of the tumor to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Mortality and morbidity in two-year disease-free survivors of small cell lung cancer after treatment with combination chemotherapy with or without irradiation.

We evaluated the long-term outcome of 148 patients with small cell lung cancer (SCLC) who had been entered into clinical trials of chemotherapy with or without thoracic and prophylactic cranial irradiation (PCI) between 1981 and 1987. Eighteen patients (12%) survived for 2 or more years. With a minimum follow-up of 4.5 years, 10 of the 18 patients who remained disease-free at 2 years are currently alive and free of SCLC. Seven of these 10 patients currently function as they did before diagnosis. However, three suffer from central nervous system changes of varying degrees in severity which appeared 2-3 years after PCI. Eight of the 18 patients who were disease-free at 2 years have died. Two died of isolated relapse in the brain at 3.6 and 4.2 years after initiation of chemotherapy. Five died of other malignancies while continuing their complete response to SCLC; two of non-small cell lung cancer, two of acute myelogenous leukemia, and one of hepatocellular carcinoma. Another patient died of an unrelated disease without any evidence of SCLC. A small but substantial proportion of patients who underwent intensive treatment will achieve long-term survival; however, these patients remain at higher risk for second cancers and late toxicities. Therefore, attention must be directed to defining the safest way to employ such treatment in the management of SCLC.

Adult↗
PubMed1993

Long-term results of combination chemotherapy with or without irradiation in small cell lung cancer: a 5- to 11-year follow-up.

Between April 1981 and December 1987, 148 patients with newly diagnosed small cell lung cancer (SCLC) were treated using combination chemotherapy with or without thoracic irradiation and prophylactic cranial irradiation (PCI) in a series of cooperative therapeutic trials. With a minimum follow-up of 4.7 years, 13 (9%) patients survived and were free of SCLC. These included 11 (15%) of 76 patients with limited disease and two (3%) of 72 patients with extensive disease. Three died without any evidence of SCLC (one each from second leukemia, non-small cell lung cancer, and unrelated disease). The remaining 10 (7%) patients are currently alive and free of SCLC beyond 4.7 years. Since late relapse beyond 5 years is a very rare event, these patients may have been cured. However, late toxicity of PCI must be kept in mind. Three among the 10 patients have suffered from neuropsychologic symptoms of varying degrees in severity. Although the long-term survival rate is a benchmark in the treatment of SCLC, modifications of therapy that may potentially avoid such toxicities should be considered hereafter.

Aged↗
PubMed1993

[CAV-PVP chemotherapy and sequential thoracic irradiation (TI) for patients with limited (LD) small cell lung cancer (SCLC)].

In order to assess the effectiveness of sequential TI for the treatment of LD SCLC, we analyzed 69 patients who had received CAV-PVP chemotherapy consisting of cyclophosphamide, adriamycin, vincristine, cisplatin and etoposide, plus sequential TI between 1986 and 1992. TI was delivered at a total dose of 50 Gy, 5 fractions/week for 5 weeks, once patients achieved a maximal response to chemotherapy. Responding patients also received PCI at a total dose of 30 Gy, 5 fractions/week for 3 weeks. Thirty patients achieved CR by chemotherapy and an additional 10 achieved CR after TI, resulting in a CR rate of 58.0%. Of 40 patients achieving CR, 24 have relapsed so far; the primary (in 15) and the brain (in 4) were the major sites of relapse despite TI and PCI. The median survival time was 18.4 months, with a 2-year survival rate of 39% and 3-year survival rate of 20%. Almost all the patients encountered grade 3 or grade 4 leukopenia while receiving chemotherapy, but the toxicity of TI was generally mild. This treatment is useful for patients with LD SCLC.

Adult↗