Biomedical subjects

R Maekawa

Publications and source records attributed to R Maekawa.

At least 19 recordsLinked to original sources

PubMed2001

Sequence-dependent antitumor efficacy of combination chemotherapy with nedaplatin, a newly developed platinum, and paclitaxel.

We evaluated the sequence dependency of antitumor efficacy and toxicity in combination therapy of nedaplatin (NDP) with paclitaxel (TXL) against Lewis lung carcinoma. The sequential administration of NDP prior to TXL (NT therapy) resulted in severe body weight loss followed by frequent toxic death of mice. In contrast, the sequential dosing of TXL prior to NDP (TN therapy) resulted in synergistically enhanced inhibition of tumor growth with less toxicity compared with the NT therapy. Comparing the antitumor activity of NDP plus TXL with that of cisplatin (CDDP) plus TXL or carboplatin (CBDCA) plus TXL, the combination effect of NDP plus TXL was significantly higher than that of CDDP plus TXL or CBDCA plus TXL. These results indicate that the TN therapy may have significant potential in clinical use.

Animals↗

PubMed2001

Processing of beta-dystroglycan by matrix metalloproteinase disrupts the link between the extracellular matrix and cell membrane via the dystroglycan complex.

The dystroglycan complex is a membrane-spanning complex composed of two subunits, alpha- and beta-dystroglycan. alpha-dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix (ECM), whereas beta-dystroglycan is an integral membrane protein which anchors alpha-dystroglycan to the cell membrane. The dystroglycan complex provides a tight link between the ECM and cell membrane. Dysfunction of the dystroglycan complex has commonly been implicated in the molecular pathogenesis of severe forms of hereditary neuromuscular diseases, including Duchenne muscular dystrophy, Fukuyama-type congenital muscular dystrophy and sarcoglycanopathy (LGMD2C, -D, -E and -F). To begin to clarify the pathway by which the dysfunction of the dystroglycan complex could lead to muscle cell degeneration, we investigated the proteolytic processing of the dystroglycan complex in this study. We demonstrate that (i) a 30 kDa fragment of beta-dystroglycan is expressed in peripheral nerve, kidney, lung and smooth muscle, but not skeletal muscle, cardiac muscle or brain, and (ii) this fragment is the product of proteolytic processing of the extracellular domain of beta-dystroglycan by the membrane-associated matrix metalloproteinase (MMP) activity. Importantly, furthermore, we demonstrate that this processing disintegrates the dystroglycan complex. Our results indicate that the processing of beta-dystroglycan by MMP causes the disruption of the link between the ECM and cell membrane via the dystroglycan complex, which could have profound effects on cell viability. Based on these and previously reported findings, we propose a hypothesis that this processing may play a crucial role in the molecular pathogenesis of sarcoglycanopathy.

Animals↗

PubMed2001

Antitumor effect of a new selective matrix metalloproteinase inhibitor, MMI-166, on experimental pancreatic cancer.

The antitumor effect of a new matrix metalloproteinase inhibitor, MMI-166, which is a selective inhibitor of MMP-2 and -9, was examined in the hamster pancreatic cancer cell line PGHAM-1. In vitro, MMI-166 inhibited the gelatinase activity of MMP-2 and -9 derived from PGHAM-1 cells, and dose-dependently inhibited invasion of PGHAM-1 through a basement membrane-like barrier. MMI-166 showed no apparent cytotoxicity to PGHAM-1 cells in culture at 100 microgram/ml. MMI-166 (200 mg/kg) or vehicle were administered orally, once daily, from day 1 until day 21 after implantation in the orthotopic implantation model of PGHAM-1. MMI-166 significantly reduced the incidence of liver surface metastasis from 66.7% to 20.0%, and it reduced the number of liver surface metastases per animal from 6.17 to 2.00, but this reduction was not significant. MMI-166 significantly reduced the volume of pancreatic tumors from 718.3 +/- 220.0 mm(3) to 222.8 +/- 85.4 mm(3). Treatment of pancreatic tumors with MMI-166 caused a significant reduction in the microvessel density from 37.90 +/- 10.18/mm(2) to 16.16 +/- 3.15/mm(2) and a significant increase in apoptotic index from 1.75 +/- 0.41% to 3.96 +/- 0.38%, but there was no significant difference between tumor cell proliferation in the MMI-166-group and the control group. These results showed that selective MMP inhibition could limit both cancer spread and angiogenesis in pancreatic cancer. The selective MMP-2 and -9 inhibitor MMI-166 may be of therapeutic use in the treatment of pancreatic cancer because of its inhibitory effect on invasion and angiogenesis.

Animals↗

PubMed2001

Preclinical in vivo antitumor efficacy of nedaplatin with gemcitabine against human lung cancer.

The antitumor efficacy of the combination of nedaplatin (NDP) with gemcitabine (GEM) was evaluated. We also compared the antitumor activity of NDP plus GEM with that of cisplatin (CDDP) plus GEM or carboplatin (CBDCA) plus GEM. Ma44, which is a human lung cancer sensitive to GEM, and NCI-H460, which is a human lung cancer refractory to GEM, were used in this study. GEM was injected i.v. once followed by i.v. injection of NDP at an interval of approximately 30 min into tumor-bearing athymic mice. GEM was administered again 3 or 4 days thereafter. Combined dosing of NDP with GEM resulted in synergistically enhanced inhibition of tumor growth in the Ma44 tumor model. NDP plus GEM was also effective against Ma44 cells when given late in the therapy, a model for advanced disease. Potent augmentation of growth inhibition by NDP with GEM was also found with the NCI-H460 tumor model. The combination effect of NDP plus GEM appeared to be superior to that of CDDP plus GEM or CBDCA plus GEM in both tumor models. Toxicity in terms of blood cell numbers was not enhanced by the combination of NDP with GEM. These results suggest the effectiveness of combination of NDP with GEM for clinical therapy.

Animals↗

PubMed2000

Anti-metastatic efficacy and safety of MMI-166, a selective matrix metalloproteinase inhibitor.

The anti-metastatic efficacy and safety of a newly-developed matrix metalloproteinase (MMP) inhibitor were examined. MMI-166, a N-sulfonylamino acid derivative, inhibited the enzyme activity of MMP-2, 9, and 14 but not MMP-1, 3 or 7. Daily oral administration of MMI-166 resulted in potent inhibition of metastatic lung colonization of Lewis lung carcinoma injected via the tail vein and liver metastasis of C-1H human colon cancer implanted into the spleen at inhibition levels of 43% and 63%, respectively. Daily administration of MMI-166 also resulted in prolonged survival of mice given intraperitoneal implantation of Ma44 human lung cancer cells. The anti-metastatic activity of MMI-166 was as effective as that of other MMP inhibitors with broad inhibitory spectrum. MMI-166 did not affect in vitro tumor cell growth. Neither body weight losses nor hematotoxicity was observed during long-term treatment, indicating the safety of MMI-166 in mice. These results indicate that the selective MMP inhibitor MMI-166 has therapeutic potential as an anti-metastasis agent.

Animals↗

PubMed2000

Improved in vivo antitumor efficacy and reduced systemic toxicity of carboxymethylpullulan-peptide-doxorubicin conjugates.

The antitumor efficacy of the conjugate of doxorubicin (DXR) and carboxymethylpullulan (CMPul) with Phe-Gly spacer (CMPul-FG-DXR) was evaluated using murine tumor models and compared with that of DXR. The conjugate exhibited higher antitumor efficacy against Lewis lung carcinoma than DXR. Complete tumor regression followed by long-term tumor-free survival was frequently observed when CMPul-FG-DXR was administered i.v. three times at a dose equivalent to 10 mg / kg of DXR. The superior survival as well as anti-metastatic effect of CMPul-FG-DXR in comparison with DXR was also demonstrated with the M5076 murine reticulosarcoma model. Body weight loss in mice treated with the conjugate was less than that in the DXR-treated group, indicating lower systemic toxicity of CMPul-FG-DXR. Simply mixing CMPul with DXR did not enhance the antitumor activity of DXR, showing that the conjugation of DXR with CMPul is necessary for improved antitumor activity. However, no enhanced antitumor efficacy of the conjugates was observed against a non-solid tumor model such as P388 leukemia. In summary, improved antitumor efficacy with reduced systemic toxicity of CMPul-FG-DXR was demonstrated in the present study. CMPul-FG-DXR may be useful as a cancer chemotherapy agent against solid tumors and metastases.

Animals↗

PubMed2000

Inhibition of gelatinolytic activity in tumor tissues by synthetic matrix metalloproteinase inhibitor: application of film in situ zymography.

Inhibition of gelatinolytic activity in implanted tumor tissues by oral administration of N-biphenyl sulfonyl-phenylalanine hydroxamic acid (BPHA), a selective matrix metalloproteinase (MMP) inhibitor, was demonstrated by means of film in situ zymography (FIZ). Active-MMP-2 but not pro-MMP-2 showed gelatinolytic activity in FIZ, whereas both forms of MMP-2 were found to be active in conventional zymography. A mixture of either tissue inhibitors of metalloproteinase-2 or BPHA with active-MMP-2 resulted in inhibition of gelatinolytic activity in FIZ but not in zymography. Thus, FIZ, but not zymography, could detect net MMP activity in tumor tissues. When a specimen from Ma44 human lung cancer xenograft was subjected to FIZ, gelatinolytic activity was markedly detected with precise localization in the tumor tissues. The gelatinolytic activity detected in Ma44 tumor tissues was found to be mainly derived from MMPs because the gelatin-degrading activity was inhibited by pretreatment of the tumor specimen with MMP inhibitors. Oral administration of BPHA but not (-)BPHA, an enantiomer of BPHA lacking MMP inhibitory activity, successfully inhibited the MMP activity localized in Ma44 tumor tissues in both a dose-dependent and time-dependent manner. The data presented in this report showed for the first time that oral administration of synthetic MMP inhibitor could inhibit the net activity of MMP activity in tumor tissues, suggesting the usefulness of the FIZ technique for determining the effective dose of MMP inhibitor in clinical studies.

Animals↗

PubMed1999

Correlation of antiangiogenic and antitumor efficacy of N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA), an orally-active, selective matrix metalloproteinase inhibitor.

The antiangiogenic activity and antitumor efficacy of a newly developed matrix metalloproteinase (MMP) inhibitor were examined. N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA) potently inhibits MMP-2, -9, and -14, but not MMP-1, -3, or -7. In contrast, (-)BPHA, an enantiomer of BPHA, was inactive against all MMPs tested. Daily oral administration of 200 mg/kg BPHA, but not (-)BPHA in mice resulted in potent inhibition of tumor-induced angiogenesis, primary tumor growth, and liver metastasis. The growth inhibition activity of BPHA was 48% and 45% in a B16-BL6 melanoma and F2 hemangio-endothelioma model, respectively. BPHA also showed 42% inhibition of the liver metastasis of C-1H human colon carcinoma cells. These results indicate that selective MMP inhibition is correlated with antiangiogenic and antitumor efficacy and that the selective MMP inhibitor BPHA has therapeutic potential.

Animals↗

PubMed1999

Combination chemotherapy with nedaplatin and cyclophosphamide in human ovarian cancer model.

The antitumor efficacy of the combination of nedaplatin (NDP) with cyclophosphamide (CPM) was evaluated using human ovarian cancer models. Since NDP has been found to have greater antitumor activity and lower nephrotoxicity than cisplatin (CDDP), we also compared the antitumor activity of NDP plus CPM with that of CDDP plus CPM. Increasing doses of NDP (16.5, 33 and 66 mg/kg as a total dose) and a fixed amount of CPM (174 or 348 mg/kg as a total dose) were injected three times at intervals of 7 days via the tail vein into mice implanted with RMUG-S, OC9-JCK or KF-28 human ovarian cancer. Simultaneous administration of NDP with CPM resulted in markedly enhanced inhibition of tumor growth for all cancers tested. The growth inhibition and survival effect of the combination therapy of NDP with CPM against KF-28 and OC9-JCK were as potent as those of CDDP plus CPM. Neither increased hematotoxicity nor a significant difference in maximum concentration, half time or area under the curve of platinum or CPM in plasma between the single and combined treatment was found. These results suggest that the combination of NDP with CPM may be clinically effective.

Animals↗

PubMed1999

[Antiangiogenic and antitumor effect of BPHA, an orally-active matrix metalloproteinase inhibitor, in in vivo murine and human tumor model].

We examined the antiangiogenic and antitumor efficacy of a newly-developed matrix metalloproteinase (MMP) inhibitor, BPHA (N-biphenyl sulfonyl-phenylalanine hydroxiamic acid). BPHA potently inhibits MMP-2, 9 and 14 but not MMP-1, 3 or 7. In contrast, (-)BPHA, an enantiomer of BPHA, was inactive against all MMP tested. Daily oral administration of BPHA in mice resulted in potent inhibition of tumor-induced angiogenesis, primary tumor growth and liver metastasis, whereas (-)BPHA did not. These results demonstrate that selective MMP inhibition is correlated with antiangiogenic and antitumor efficacy and that the selective MMP inhibitor BPHA has therapeutic potential without hematotoxic effect or loss of body weight.

Animals↗

PubMed1998

Anticancer efficacy in vivo and in vitro, synergy with 5-fluorouracil, and safety of recombinant methioninase.

The elevated exogenous-methionine dependency of tumors for growth has been observed in all major cancer cell types. We have previously cloned a methioninase (rMETase) from Pseudomonas putida to deplete methionine. Growth inhibition followed by apoptotic cell death was induced by treatment of tumor cells with rMETase in vitro. A single i.p. injection of 300 units of rMETase can lower the serum methionine level in the mice from 70 microM to less than 1 microM within 2 h and maintain this depleted level for 8 h. Repeated dosing of rMETase of tumor-bearing mice could be administered without acute immune-hypersensitivity. rMETase treatment demonstrated growth inhibitory activity against human tumors in nude mice, including those which were multiple drug-resistant. No body weight loss or hematotoxicity, except a slight anemia, was found throughout the therapy. The combined treatment of the Lewis lung carcinoma with a fixed rMETase dose and increasing doses of 5-fluorouracil (5-FU) resulted in a dose-dependent enhanced antitumor efficacy for survival as well as tumor growth inhibition. Thus, methionine depletion by rMETase potentiates the antitumor efficacy of 5-FU. The data presented in this report thus indicate that rMETase is active alone, is synergistic in combination with 5-FU, and has negligible toxicity suggesting a novel clinical approach for effective cancer therapy.

Animals↗

PubMed1998

Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives.

Various N-sulfonylamino acid derivatives were synthesized and evaluated for their in vitro and in vivo activities to inhibit type IV collagenase (MMP-9 and MMP-2). When the amino acid residue and the sulfonamide moiety were modified, their inhibitory activities were greatly affected by the structure of the sulfonamide moiety. A series of aryl sulfonamide derivatives containing biaryl, tetrazole, amide, and triple bond were found to be potent and highly selective inhibitors of MMP-9 and MMP-2. In addition, these compounds were orally active in animal models of tumor growth and metastasis. These results revealed the potential of the N-sulfonylamino acid derivatives as a new type of candidate drug for the treatment of cancer.

Administration, Oral↗

PubMed1998

Sequence-dependent antitumour efficacy of combination chemotherapy of nedaplatin, a novel platinum complex, with 5-fluorouracil in an in vivo murine tumour model.

The antitumour efficacy of a sequential combination of nedaplatin (NDP) and 5-fluorouracil (5-FU) was evaluated using Lewis lung carcinoma in vivo. NDP was developed as a second generation platinum complex. Because it has greater antitumour activity and lower nephrotoxicity than cisplatin (CDDP), we also compared the antitumour activity of NDP plus 5-FU with that of CDDP plus 5-FU. A fixed 5-FU dose was injected daily for 5 days and increasing doses of either NDP or CDDP were injected once via the tail vein into the Lewis lung carcinoma-implanted mice. The sequential administration of either NDP or CDDP prior to 5-FU (NF or CF therapy) resulted in severe body weight loss followed by the death of the tumour-bearing mice when the high-dose of NDP or CDDP was administered. In contrast, the sequential administration of 5-FU prior to NDP or CDDP (FN or FC therapy) resulted in synergistically enhanced inhibition of tumour growth and prolonged survival in comparison with NDP, CDDP or 5-FU monotherapy. At the high-dose of NDP in FN therapy, a reduction of tumour size and long-term tumour-free survival were frequently observed. The survival effect of the combinations of NDP with 5-FU was superior to those of the combination of CDDP with 5-FU. In conclusion, the sequence-dependent antitumour efficacy and toxicity of the combination of NDP or CDDP with 5-FU was demonstrated in this study, and FN therapy appeared to be the most efficient regimen as a clinical therapy.

Animals↗

PubMed1998

[Augmented antitumor activity in combination chemotherapy of nedaplatin with etoposide].

Augmented antitumor activity in combination chemotherapy of Nedaplatin (NDP) or Cisplatin (CDDP) with Etoposide (ETP) against murine and human lung cancer cells was demonstrated. NDP and CDDP were administered once and ETP daily for five days via tail vein. In the mice bearing Lewis lung carcinoma, a combination of NDP and ETP resulted in synergistically enhanced inhibition of tumor growth, and prolonged survival in comparison with either NDP or ETP alone. NDP showed a more potent combination effect with ETP than CDDP did. These effects were also demonstrated in human lung cancer cell lines. Although body weight loss was enhanced by the combination of NDP or CDDP with ETP, it was tolerable, and no significant difference between NDP plus ETP and CDDP plus ETP was observed. Thrombocytopenia was not enhanced in the combined treatment of NDP with ETP. These results suggest the usefulness of the combination of NDP with ETP as a clinical therapy for lung cancer.

Animals↗

PubMed1998

[Augmented antitumor efficacy of combination chemotherapy of nedaplatin with 5-fluorouracil in in vivo murine and human tumor model].

Augmented antitumor activity was demonstrated in combination chemotherapy of Nedaplatin (NDP) or Cisplatin (CDDP) with 5-fluorouracil (5-FU) against murine lung carcinoma and human squamous carcinoma from head and neck. Either NDP or CDDP (1/4 to 1 maximum tolerated dose; MTD) was injected once and 5-FU (1/16 MTD) was injected daily for five days via tail vein to tumor-implanted mice. The sequential administration of either NDP or CDDP prior to 5-FU (NF or CF therapy) showed severe body weight loss followed by the toxic death of tumor-bearing mice at the MTD of NDP or CDDP. In contrast, the reverse sequence of the treatment, that is, 5-FU prior to NDP or CDDP (FN or FC therapy), resulted in the synergistically enhanced inhibition of tumor growth and the prolonged survival in comparison with NDP, CDDP or 5-FU monotherapy. The antitumor activities of the combinations of CDDP with 5-FU was less than those of the combination of NDP with 5-FU. Especially, at the MTD of NDP in FN therapy, long-term tumor-free survival was frequently observed. Thus, FN therapy was thought to be the most efficient regimen in combination of NDP with 5-FU as a clinical therapy.

Animals↗

PubMed1993

Establishment of highly metastatic tumor clones derived from a skin squamous cell carcinoma (SqC-NH), D-1 and F-3, with distinct features of pulmonary metastases.

We have established two highly metastatic tumor clones, D-1 and F-3, which have the distinct features of undergoing pulmonary metastases. Both clones were derived from a skin squamous cell carcinoma (SqC-NH), which had spontaneously occurred in DS-Nh mice. F-3 was morphologically spindle-shaped in tumor mass and adherent in culture, while D-1 was round and non-adherent. In in vitro growth, there was no significant difference between them. When the clonal tumor cells were implanted intradermally into syngeneic mice, however, the growth of D-1 was slower than that of F-3. As for the metastatic ability, both D-1 and F-3 were highly metastatic compared with the original tumor. Interestingly, the pulmonary metastases of these two clones were apparently different. In F-3-bearing mice, some round nodules were detected and no tumor cells were seen in the surrounding area around the nodules (nodule-type). In contrast, D-1 cells had initially grown from the periphery of lobes, and interstitially infiltrated the lung parenchyma area without forming nodules (diffuse-type) and the appearance was similar to lymphagitis carcinomatosa. Histologically, a remarkably smaller number of metastatic foci formed around the blood vessel for D-1 as compared with F-3. It should also be noted that some localized nodules (nodule-type both visually and histologically) were seen in the lung, when D-1 cells were inoculated in the tail vein. In addition, D-1 showed markedly higher lymphatic metastasis than F-3. These observations show that the pulmonary metastases of D-1 and F-3 differ in the mechanisms underlying the processes of tumor dissemination. We suppose a possibility that D-1 may preferentially metastasize via the lymphatics and F-3 may metastasize via the bloodstream.

Animals↗

PubMed1992

Human cytomegalovirus in the pancreas of patients with type 2 diabetes: is there a relation to clinical features, mRNA and protein expression of insulin, somatostatin, and MHC class II?

Human cytomegalovirus (HCMV) was recently demonstrated in the pancreas of about half the patients with type 2 diabetes mellitus in the absence of mumps, rubella or Coxsackie B virus. The present study addresses the question as to whether type 2 diabetes with an HCMV-positive pancreas differs from those with HCMV-negative pancreases with respect to age, sex, treatment, duration of disease, volume densities of B-cells and D-cells, mRNA levels of insulin and somatostatin, islet amyloid peptide deposits and major histocompatibility complex (MHC) class I and class II gene transcription, and protein expression. HCMV-positive type 2 diabetic patients showed a tendency towards a shorter duration of disease and significantly increased levels of MHC class II on RNA. In addition, expression of MHC class II product (HLA-DR) was identified in duct epithelial cells and/or islet cells in 9 diabetic pancreases and in 2 non-diabetic glands. No MHC class I expression could be detected. No other clinical differences between HCMV-positive and HCMV-negative glands were found. All 10 HCMV-positive diabetics showed a strong expression of MHC class II mRNA in the pancreas. By immunocytochemistry, 4 of 10 demonstrated expression on the islets; three of ten also expressed MHC DR beta on ductal cells. This finding might be related to the viral infection, as only 2 of the 9 HCMV-negative patients were HLA-DR beta positive and none of the non-diabetic controls showed increased levels of MHC class II mRNA. These data suggest that HCMV infection in the pancreas is associated with type 2 diabetes. However, no conclusions as to a role of this virus in the aetiopathology of type 2 diabetes can be drawn at present.

Aged↗

PubMed1992

A case of an undifferentiated small cell carcinoma of the esophagus with a primary abdominal mass.

This paper reports a case with an undifferentiated carcinoma of the esophagus which primarily developed symptoms due to metastatic lesions. The case was a 59-year-old woman with a primary manifestation of an abdominal mass and with subsequent dysphagia. A protruding lesion with ulceration was found at the lower third of the thoracic esophagus by endoscopic examination and was histologically proved to be an undifferentiated carcinoma by biopsy. The abdominal mass was initially thought to be due to metastasis to an abdominal lymph node based on the diagnosis image finding at admission, but it was consequently found by autopsy to be a metastatic tumor in the liver. Therefore, undifferentiated carcinoma of the esophagus should be take into account for differential diagnosis of an abdominal mass.

Abdominal Neoplasms↗