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Biomedical subjects

O Abe

Publications and source records attributed to O Abe.

At least 73 records · Page 4Linked to original sources
PubMed1993

[Phase II study of NK 622 (toremifene citrate) in advanced breast cancer, a multicentral cooperative dose finding study].

In order to determine the usual dose in the first line therapy and a high dose in the second or third line therapy, a dose finding study of a novel antiestrogen NK 622 (toremifene citrate) was performed in patients (pts) with advanced or recurrent breast cancer. NK 622 was orally administered daily once for more than 8 weeks. In pts without previous drug therapy or in pts with cancer relapse after adjuvant therapy, the response rates [(CR + PR)/total] were 24.1% (7/29), 13.8% (4/29), 20.0% (1/5) and 40.0% (2/5) at doses of 40, 60, 120 and 240 mg/day, respectively. A 40 mg/day dose showed an objective response only in postmenopausal pts with estrogen receptor (ER) positive or unknown cancer. At a dose of 60 mg/day, some of the responding cases were premenopausal pts or pts with ER(-) cancer. In pts with cancer relapse during adjuvant therapy or in those with previous therapy and/or radiation, response rates were 25.0% (2/8), 0% (0/4), 13.5% (5/37) and 10.3% (4/39) at doses of 40, 60, 120 and 240 mg/day, respectively. Response was more frequent in pts with ER (+) cancer than with ER (-) cancer. The response rates in pts with previous therapy including tamoxifen (TAM) except medroxyprogesterone (MPA) were 14.3% (4/28) at a 120 mg/day dose and 6.1% (2/33) at a 240 mg/day dose. In pts with previous therapy including TAM, MPA and other antitumor agents, the rate was 18.2% (2/11) at a 120 mg/day dose. Side effects such as elevation of GOT, GPT and serum Ca level, decrease of hemoglobin, anorexia, nausea/vomiting, fatigue, dizziness and hot flush were observed. These side effects were moderate in grade and reversible. Dose dependency of side effects was not clearly observed in grade and incidence. From these results, NK 622 is expected to be a safe drug with efficacy in first line therapy at a dose of 40 mg/day and in second or third line therapy at a dose of 120 mg/day.

Administration, Oral↗
PubMed1993

[Efficacy and safety of high dose NK 622 (toremifene citrate) in tamoxifen failed patients with breast cancer].

Efficacy and safety of high dose administration of NK 622 (toremifene citrate) were studied in tamoxifen (TAM)--failed patients with breast cancer. The patients included in the study were the following failure cases in TAM therapy: unresponded cases in TAM therapy (TAM unresponded cases), temporary responded (CR, PR) but progressed cases in TAM therapy (TAM temporary responded cases), and those relapsing during TAM adjuvant therapy or within 6 months after the adjuvant therapy (TAM adjuvant failed cases). NK 622 of a 120 mg/day dose were orally given daily once at least for 8 weeks. The response rates in evaluable cases were 6.3% (1/16) in TAM unresponded cases, 11.1% (1/9) in TAM temporary responded cases, 15.4% (4/26) in TAM adjuvant failed cases, and 11.8% (6/51) in total cases including 1 CR and 5 PR cases. Long NC in which duration of NC maintained for more than 6 months was observed in 18.8% (3/16) of TAM unresponded cases, 22.2% (2/9) of TAM temporary responded cases, 11.5% (3/26) of TAM adjuvant failed cases, and 15.7% (8/51) of total cases. Rates of response and long NC were 14.3 and 19.0% in postmenopausal patients with estrogen receptor positive cancer, respectively. A median value of duration to the onset of response was 34 days (15-137). Median duration of response and long NC were 127 days (39-381) and 238.5 days (178-281), respectively. Adverse effects were experienced in 3 (5.1%) of 59 patients: nausea in 1, vertigo in 1 and increase of GOT, GPT, LDH and gamma-GTP in another 1. The side effects were moderate and reversible. From these results, NK 622 seems to become a safe and effective drug for TAM-failed patients with breast cancer by using a 120 mg/day dose.

Administration, Oral↗
PubMed1993

[Clinical evaluation of NK 622 (toremifene citrate) in advanced or recurrent breast cancer--a comparative study by a double blind method with tamoxifen].

Efficacy and safety of NK 622 (toremifene citrate) were compared with tamoxifen (TAM) by a double blind test in patients with advanced or recurrent breast cancer. NK 622 and TAM were given orally for 12 weeks or more at daily doses of 40 and 20 mg/body, respectively. Eligible cases in NK622 and TAM groups were both 57 patients. No significant difference was observed in patient characteristics between either group. Response rates were 26.3% (8 CR and 7 PR, 15/57) in the NK 622 group and 28.1% (3 CR and 13 PR, 16/57) in the TAM group. Median values of duration to onset of CR were 91 days in the NK 622 group and 169 days in the TAM group. The duration was significantly shorter with the NK 622 group. Median duration of efficacy in CR and PR cases was 155 days in the NK 622 group and 154.5 days in the TAM group. Adverse effects were encountered in 7 patients (12.3%) of each of the 2 groups. The side effects were fatigue, hot flush, WBC decrease, abnormal values in liver function tests, etc. in the NK 622 group and anorexia, nausea, eruption, feeling of warmth, sweating, dry mouth, dizziness, abnormal values in liver function tests, etc. in the TAM group. Administration was discontinued in one patient with eruption and another patient with abnormal values of liver function tests in the TAM group, while there was no such case in the NK 622 group. Including the discontinued cases, the side effects were moderate and reversible in both groups. The patients in whom a drug was determined as useful or more numbered 24/57 (42.1%) in the NK 622 group and 23/57 (40.4%) in the TAM group. There was not significant difference between the 2 groups in the above results except the duration to onset of CR. From these results, NK 622 is expected to show comparable efficacy, safety, and usefulness in patients undergoing TAM treatment for advanced or recurrent breast cancer.

Administration, Oral↗
PubMed1992

Growth-inhibitory action of an estrogen-chlorambucil conjugate (KM2210) in human breast cancer cell line MCF-7: its relation to reduction of estrogen receptor and transforming growth factor-alpha secretion.

We investigated the effects of a benzoate of an estradiol-chlorambucil conjugate (KM2210) and chlorambucil on growth, estrogen receptor, and secretion of transforming growth factor (TGF)-alpha in the hormone-dependent human breast cancer cell line MCF-7. In the presence of 10(-10)-10(-6) M KM2210, the estrogen-induced growth of MCF-7 was completely inhibited. Inhibited growth of MCF-7 treated with 10(-8) or 10(-6) M KM2210 for 4 days was not rescued by removal of the drug and the addition of estradiol. By treatment of MCF-7 with KM2210 for 4 days, estrogen receptor-binding sites were decreased at 10(-8) M and were not detected at 10(-6) M but were unaltered by 10(-8) M chlorambucil. Moreover, estrogen receptor immunoreactivity and the level of estrogen receptor mRNA were decreased through treatment with 10(-6) M KM2210 for 4 days. These suppressions occurred prior to the onset of inhibitory action on MCF-7 growth. Secretion of TGF-alpha from MCF-7 was decreased by 4 days of treatment with 10(-8) and 10(-6) M KM2210 but not with chlorambucil. The addition of exogenous TGF-alpha generally restored the growth of MCF-7 treated with 10(-8) M KM2210. We concluded that KM2210 has irreversible or at least long-standing inhibitory effect on estrogen-dependent growth of MCF-7. It is conceivable that the decrease of estrogen receptor renders the cell unable to respond to estrogen with increased TGF-alpha secretion and succeeding cell growth.

Antineoplastic Agents↗
PubMed1992

Endogenous urinary 3-hydroxyproline has 96% specificity and 44% sensitivity for cancer screening.

A method for determining the endogenous urinary excretion levels of both 3-hydroxyproline and 4-hydroxyproline that may be useful for cancer screening of the general population and at the workplace is evaluated in this report. The excretion levels of 3-hydroxyproline and 4-hydroxproline were estimated in 97 patients with cancer and in 99 patients with various nonmalignant diseases and were compared with those of 211 healthy persons. Measurable 3-hydroxyproline peaks (by amino acid autoanalyzer) were absent from 93 samples from 211 healthy persons (44%), 50 of 99 patients with nonmalignant disease (50%), and 10 of 96 patients with cancer (10%). The levels of both 3-hydroxyproline and 4-hydroxyproline in cancer patients were significantly higher than those in healthy persons (p < 0.001 and p < 0.01, respectively) and those in patients with nonmalignant diseases (p < 0.05 and p < 0.01, respectively). Cancer patients were classified into three groups according to grade of cancer growth and invasion. The sensitivity of 3-hydroxyproline was 44% and higher than that of 4-hydroxyproline for the detection of stage II cancers (no distant metastasis); the sensitivities of both hydroxyprolines for the detection of stage I (very early cancer) were low. The specificity of these assays for healthy persons and patients with nonmalignant disease was 96% and 92% for 3-hydroxyproline, and 97% and 79% for 4-hydroxyproline, respectively. Urinary 3-hydroxyproline level should be further investigated as a cancer screening method for healthy persons in the community or the workplace, but appears unlikely to detect many cancers in the earliest stages.

Adult↗
PubMed1992

[Phase I study of NK 622 (toremifene citrate)].

A phase I study of NK 622 (toremifene citrate), a novel antiestrogen, was conducted in female patients with cancer. Patients received a single oral dosing or daily once oral dosing for five consecutive days. Any adverse effects were not experienced in the single dosing of 40 or 60 mg of NK 622. In the daily administration of 10, 20, 40, 60, 120, 240 and 480 mg/day, one of three patients who received 20 mg/day experienced grade 1 anorexia, three of four patients received 240 mg/day experienced adverse effects: Grade 1 leukopenia in one patient, Grade 1 general hot flush in one patient, and Grade 1 nausea, hot flush in the face and vertigo, Grade 2 anorexia, fatigue, dull headache and general hot flush in another one patient. These symptoms recovered to normal levels after treatment. Serum hormone levels were examined in postmenopausal patients, and a significant increase of the sex hormone binding globulin level was observed in the patients received 120 and 240 mg/day doses. Serum levels of NK 622 determined as free base (TOR) reached the peak levels in 2 to 4 hours after administration on the 1st and 5th day in daily treatment, while a metabolite N-demethyltoremifene (TOR-1) reached the peak level in 4 to 170 hours. Maximum serum levels and area under the concentration versus time curves of TOR and TOR-1 increased dose-dependently. These values also increased by repetition of the treatment. Half-lives of TOR and TOR-1 in serum ranged in 74.5 to 148.9 hours and 154.1 to 653.1 hours, respectively. From these results, it was concluded that safety and efficacy of NK 622 should be assessed by using 240 mg or less doses in clinical phase II studies where breast cancer patients received long term treatment with NK 622.

Administration, Oral↗
PubMed1991

Cancer cachexia syndrome developed in nude mice bearing melanoma cells producing leukemia-inhibitory factor.

Melanoma-derived lipoprotein lipase inhibitor (MLPLI) is a factor purified from the conditioned medium of a human melanoma cell line, SEKI, which induced severe cachexia in tumor-bearing nude mice. Amino acid sequencing revealed that the amino-terminal portion was identical to that of leukemia-inhibitory factor (LIF). To determine whether MLPLI is actually LIF, the expression of LIF mRNA was examined in the SEKI melanoma cell line. Northern blot analyses revealed that the cell line displayed an intense hybridizable band with a molecular size of 3.8 kilobases, suggesting that MLPLI is identical to LIF. The relationship between the development of the cancer cachexia syndrome and the expression of LIF mRNA was examined in four melanoma xenografts, SEKI, G361, A375 and MEWO, in nude mice. SEKI- and G361-bearing nude mice developed cancer cachexia syndrome, and their body weights decreased by the 25th day after the transplantation to 73.6% and 73.8% of the control, respectively. A375- and MEWO-bearing nude mice, however, did not develop the syndrome. Northern blot analyses revealed that G361 as well as SEKI expressed a large amount of LIF mRNA, but A375 and MEWO did not, suggesting a close relationship between the expression of LIF mRNA and the development of the syndrome. These data support the concept that MLPLI, or LIF, plays an important role in the development of the cancer cachexia syndrome observed in melanoma-bearing nude mice.

Animals↗
PubMed1991

Endothelin-1 inhibits adipogenic differentiation of 3T3-L1 preadipocytes.

The effect of endothelin (ET)-1 on the adipogenic differentiation of 3T3-L1 preadipocytes was examined. Cellular morphology and lipoprotein lipase activity were used as differentiation markers. ET-1 inhibited the hormone-induced adipogenic differentiation of 3T3-L1 preadipocytes morphologically and biochemically in a dose-dependent manner. These findings promote ET-1 as a potent inhibitor of adipogenic differentiation, playing an important role in cellular differentiation of preadipocytes and making it a significant regulator of lipid metabolism.

Adipose Tissue↗
PubMed1991

Location of the disulfide bonds in the antitumor protein neocarzinostatin.

Two disulfide bonds in the antitumor antibiotic neocarzinostatin were determined chemically. The peptic and peptic/thermolytic peptides from the native protein were isolated by gel filtration and ion-exchange chromatography followed by reverse-phase HPLC. The cystine peptides obtained were oxidized separately by performic acid treatment and further separated by HPLC into cysteic acid peptides. Sequence analyses of the isolated peptides revealed the location of the disulfide bonds at Cys37-Cys47 and Cys88-Cys93.

Amino Acid Sequence↗
PubMed1991

In vitro and in vivo antitumor effects of murine monoclonal antibody NCC-ST-421 reacting with dimeric Le(a) (Le(a)/Le(a)) epitope.

A murine monoclonal antibody (MAb), NCC-ST-421 (IgG3), was raised by using a human gastric cancer xenograft St-4 as immunogen. Immunization was achieved by transferring immunocompetent normal BALB/c mouse spleen cells into BALB/c-nu/nu mice bearing St-4 tumors. Hybridomas were produced from spleen cells of the mice after rejection of the tumors and were screened for preferential reactivity with cancers on formalin-fixed paraffin sections, as described previously for establishment of MAb NCC-ST-439 (M. Watanabe et al., Jpn. J. Cancer Res., 76: 43-52, 1985). The immunobiological and immunochemical properties of the new MAb NCC-ST-421 are described here. The MAb is essentially directed to a structure with dimeric Le(a) (V4III4Fuc2Lc6Cer) epitope (Gal beta 1----3[Fuc alpha 1----4]GlcNAc beta 1----3Gal beta 1----3[Fuc alpha 1----4]GlcNAc beta 1----3Gal beta 1----4Glc beta 1----1 Cer). It cross-reacts with Le(a) but does not show any effect on Le(a)-positive RBC in vitro or on Le(a)-positive tissue loci in vivo. ST-421 strongly induced antibody-dependent cellular cytotoxicity using human peripheral blood leukocytes as effector cells with a variety of human tumor cells, using the short-term 51Cr release assay. It also showed striking complement-dependent cytotoxicity with a human complement source and was able to produce lysis of a variety of human cancer cell lines, supporting its observed ability to cause cytotoxic suppression of tumor growth in nude mice. In another series of experiments, i.p. injection of ST-421 completely inhibited growth of human tumor xenografts in nu/nu mice, and this inhibitory activity was closely dependent on expression of the dimeric Le(a) antigen on the cell surface. While Le(a) antigen was expressed in the kidneys of nu/nu mice, infusion of ST-421 in these mice did not cause histological change in kidney tissue. This finding suggests that the MAb does not damage normal cells or tissues which contain cross-reacting Le(a) antigen. These results demonstrate that ST-421 exerts a significant antitumor effect in vitro as well as in vivo, does not affect Le(a) antigen expressed on normal tissues, and therefore has potential application in therapy of certain types of human cancer which express the dimeric Le(a) antigen.

Animals↗
PubMed1991

Significance of int-2/hst-1 coamplification as a prognostic factor in patients with esophageal squamous carcinoma.

The correlation between the clinical outcome in patients with esophageal squamous cell carcinoma and coamplification of the proto-oncogenes int-2 and hst-1, which are partially homologous to angiogenesis-inducing fibroblast growth factor, was analyzed retrospectively. Coamplification of these genes was examined by slot-blot hybridization using DNAs extracted from formalin-fixed and paraffin-embedded blocks of tissues. These tissues were obtained from 107 patients with esophageal squamous cell carcinoma who had undergone radical surgery. Int-2/hst-1 coamplification greater than 3-fold was observed in the primary tumors of 30 of 107 cases (28%), and in the metastatic lymph nodes of 12 of 40 cases (30%). The cumulative survival rate of patients with int-2/hst-1 coamplification in the primary tumors was significantly lower than that of the patients without coamplification (P less than 0.001), and there were no significant differences between the clinicopathological backgrounds of the 2 groups. Int-2/hst-1 coamplification was also significantly correlated with a high incidence of eventual metastasis in distant organs in these patients. These results suggest that int-2/hst-1 coamplification is a new biological indicator of prognosis and distant organ metastasis in patients with esophageal squamous cell carcinoma.

Carcinoma, Squamous Cell↗
PubMed1991

Japanese early phase II study of droloxifene in the treatment of advanced breast cancer. Preliminary dose-finding study.

Droloxifene, a new tamoxifen (TAM)-derived compound, has excellent antiestrogenic activity. This compound exhibits less endogenously estrogenic but higher antiestrogenic activity, with better tolerability than TAM in experimental models. Two phase II studies of droloxifene were performed in 47 Japanese institutions to assess the optimal dose. The first was a randomized comparative study using 20, 40, and 80 mg, respectively, once a day. The other was a pilot study using 120 mg once a day. The subjects of both studies were women with primary or recurrent advanced breast cancer, regardless of estrogen receptor status and menopausal status. Of 94 patients enrolled in the comparative study, 22, 26, and 23 were evaluable in the 20-, 40-, and 80-mg groups, respectively. Of the 71 evaluable patients, 14 (19.7%) were negative for estrogen receptor, and 36 (50.7%) had a previous history of TAM therapy. The response rate complete response + partial response (CR + PR) was 13.6% for 20 mg, 15.4% for 40 mg, and 17.4% for 80 mg. The rate of no change (NC) was 31.9%, 46.1%, and 47.8%, and that of progressive disease (PD) was 54.5%, 38.5% and 34.8%, respectively, in the 20-, 40-, and 80-mg groups. In the other study, 16 patients were enrolled in the pilot study with 120 mg of droloxifene, of whom 14 were evaluable. The response rate was slightly higher: four responders (28.6%) were assessed as CR + PR, six (42.9%) as NC, and four (28.6%) as PD. These results suggest that the response rate may be dose-dependent and that PD rates seem lower in the higher doses. No serious side effects were encountered, and droloxifene was well tolerated even in the higher doses. At present, a final randomized dose-finding study with 80 mg/day and 120 mg/day is being carried out.

Adult↗
PubMed1991

Antitumor activity of fluoropyrimidines and thymidylate synthetase inhibition.

Experimental chemotherapy with 5-fluorouracil (5-FU; 60 mg/kg), 1-hexylcarbamoyl-5-fluorouracil (HCFU; 70 mg/kg), 3-(3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl)-1-ethoxym ethyl-5- fluorouracil (BOF-A2; 30 mg/kg) and UFT (20 mg/kg as tegafur with uracil at a molar ratio of 1:4) was performed using human gastric (H-111) and colon (Co-4) carcinoma strains in nude mice. 5-FU was administered ip with a q4d x 3 schedule and the other agents were given po daily for three weeks. Concentrations of 5-FU in the serum and the tumor were assessed by gas chromatography-mass fragmentography, two hours or 12 days (5-FU) after the last treatment, and thymidylate synthetase (TS) was assayed according to the method of Spears et al. using the same schedule. The antitumor activity of the agents was assessed in terms of the actual tumor weight at the end of the experiment. HCFU was effective against both strains and 5-FU was effective against Co-4, although the other agents were ineffective against either strain. Statistically significant correlations were found between the serum and tumor concentrations of 5-FU and antitumor activity. Statistically significant correlations were also observed between the antitumor activity and TS inhibition rate (TSIR) and the activity of free thymidylate synthetase (TSfree), with higher TSIR and lower TSfree resulting in higher antitumor activity. Therefore, TSIR and TSfree were thought to be promising indicators for predicting the antitumor activity of fluoropyrimidines.

Adenocarcinoma↗
PubMed1991

Appraisal of adjuvant chemoendocrine therapy with tamoxifen plus tegafur in patients with breast cancer.

To assess chemoendocrine therapy in the adjuvant treatment of patients with Stage II or III breast cancer, 228 patients were enrolled in a 12-month trial period from January 1982 to January 1983. One hundred ninety evaluable patients were followed up for five years. The regimen in this trial consisted of intravenous administration of 13 mg of mitomycin C per m2 during the operation and 6.5 mg of the same drug per m2 on the first day, and oral administration of 600 mg of tegafur per m2 alone or supplemented with 13 mg of tamoxifen per m2 for two years. No survival advantage was observed with addition of tamoxifen to tegafur in terms of five-year survival (88.7% vs 86.6% for Stage II and 69.9% vs 82.2% for Stage III). However, there was a significant prolongation of relapse-free survival among patients receiving tegafur and tamoxifen as compared with those who received tegafur alone: 72.9% vs 55.8% (p = 0.098 in the logrank test).

Adult↗
PubMed1991

[Preclinical screening of chemotherapeutic and endocrine agents using human tumor xenografts--nude mouse system].

Although newly developed antitumor agents had been screened using cultured human cell lines and rodent tumor systems, it was apparent that the positive antitumor activity of the agents on these experimental tumors is not a sufficient but a necessary condition to elucidate the antitumor activity on clinical human cancers. We have clarified that the chemosensitivity of human gastric, breast colon carcinoma xenografts could reproduce the essentially identical chemosensitivity of clinical carcinomas when the maximum tolerable doses of the conventionally available agents were administered to tumor bearing nude mice, and human breast carcinoma xenografts had a similar estrogen dependency and endocrine sensitivity to clinical human breast cancer. These findings indicated that the human tumor xenografts--nude mouse is an appropriate model to predict the clinical antitumor activity of newly developed antitumor agents.

Animals↗
PubMed1991

[Cooperative study of surgical adjuvant chemotherapy for colorectal cancer (third report): five-year results. Cooperative Study Group of Surgical Adjuvant Chemotherapy for Colorectal Cancer in Japan].

A randomized controlled study was carried out by the envelope method with 491 institutions in participation across the country in order to find an optimal surgical adjuvant chemotherapy for curatively resected colorectal cancer. The schedules for drug administration were different in four districts: ACNU + Futraful (FT) group and FT alone group in the Hokkaido-Shikoku district; the same schedule groups plus untreated group in the Chubu-Kinki district; MMC+FT group, FT alone group in the Tohoku-Kanto district; and ADM+FT group and FT alone group in the Chugoku-Kyushu district. The numbers of patients admitted to this study were 2,450 cases with colon cancer and 2,456 cases met the evaluation criteria of this study. The 5-year survival rate on the whole did not differ from combination therapy to single drug therapy in either colon cancer or rectal cancer, but in Dukes C rectal cancer the five-year survival rate tended to be higher with the combination therapies. In n2 (+) or a2(s) rectal cancer in particular, combination therapies with MMC and FT and with ADM and FT achieved significantly higher five-year survival rate, and the rate of local recurrence was significantly lower with ADM+FT.

Antineoplastic Combined Chemotherapy Protocols↗