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Biomedical subjects

N Saijo

Publications and source records attributed to N Saijo.

At least 109 records · Page 6Linked to original sources
PubMed1998

Cisplatin plus oral etoposide in the treatment of patients with advanced small cell lung cancer. Japan Clinical Oncology Group.

BACKGROUND: Etoposide is a highly schedule-dependent drug. We investigated combination chemotherapy of oral etoposide and intravenous cisplatin for small cell lung cancer (SCLC). METHODS: Fifty-seven patients with SCLC with extensive disease (ED) or limited disease (LD) with pleural effusion registered in the 21 institutions of the Japan Clinical Oncology Group were treated with oral etoposide 40 mg/m2/d for 21 days and cisplatin 80 mg/m2 on day 1 of every 28-period day. The entry period was between February 1992 and August 1995. The actual percentages of patients treated with etoposide were 93.6, 89.5, 92.3 and 96.9% in the first, second, third and fourth cycles, respectively. RESULTS: Nine patients (15.8%) achieved a complete response resulting in an overall response rate of 82.5% (95% confidence interval, 70.1-91.3%). Leukopenia and thrombocytopenia of grade 3 or 4 were observed in 36 (49.1%) and 8 (14.0%) patients, respectively. Anemia of grade 3 or 4 occurred in 28 (49.1%) patients. Nausea, vomiting, anorexia and alopecia were common adverse events. One patient died of hemoptysis due to grade 4 thrombocytopenia. The mean survival time was 47.0 weeks. CONCLUSIONS: This dose and schedule of administration of etoposide in combination with cisplatin are considered to be clinically active. However, prolonged gastrointestinal toxicity of oral etoposide was a problem in comparison with the standard etoposide platinum regimen given by intravenous administration.

Administration, Oral↗
PubMed1998

Japan Clinical Oncology Group (JCOG).

The Japan Clinical Oncology Group (JCOG) is a cooperative oncology group with the aims of conducting, developing, coordinating and stimulating clinical research in Japan on the treatment of cancer and related problems. The purpose of JCOG is to establish and improve the standard of cancer treatment, mainly in solid cancer, through the testing of new therapeutic regimens or combined modalities, using drugs that are newly-approved or already commercially available. Research sponsored by JCOG is accomplished mainly through the execution of large, prospective, randomized, multicenter, clinical trials. In this way, JCOG facilitates the passage of new clinical trial discoveries into state-of-the-art treatment.

Clinical Trials as Topic↗
PubMed1998

Factors that influence the eligibility of cases for inclusion in clinical trials. The Lung Cancer Chemotherapy Study Group of the Japan Clinical Oncology Group.

BACKGROUND: It is important to minimize the incidence of ineligible cases to improve the quality of clinical trials. To determine factors which may influence the incidence of ineligible cases, the incidence of and reasons for ineligibility in clinical trials were retrospectively analyzed. METHODS: We retrospectively examined the incidence of and reasons for ineligibility for inclusion in eight clinical trials conducted by the Lung Cancer Chemotherapy Study Group of the Japan Clinical Oncology Group and four trials financed by trust funds from a pharmaceutical company. RESULTS: In these 12 clinical studies, the incidence of ineligibility was 4.2% (32/762) (range 0-10.6%). Specific factors that might influence the incidence of ineligible cases were then analyzed. There was a significant difference in the incidence of ineligibility between the methods of registration (P < 0.05). The incidences using a central registration and without using a central registration system were 2.8% (9/322) and 5.2% (23/440) respectively. We also analyzed ineligible cases in clinical studies published in the Journal of Clinical Oncology. In clinical studies published in the Journal of Clinical Oncology recently and 10 years ago, the incidences of ineligible cases were 5.0% (942/18 878) and 4.1% (206/4995) respectively. In clinical studies on lung cancer published in the Journal of Clinical Oncology from 1984 to 1995, the incidence of ineligible cases was 4.7% (900/19,116). There was no significant difference in the incidence of ineligible cases between our 12 studies and the Journal of Clinical Oncology clinical studies by the chi 2 test (P > 0.05). CONCLUSIONS: We conclude that the incidence of ineligible cases in our studies is similar to that in clinical trials published in the Journal of Clinical Oncology. Central registration systems are useful for checking for ineligibility, and to increase the quality of clinical trials.

Clinical Trials as Topic↗
PubMed1998

Cancer chemotherapy in the elderly.

As the geriatric population is growing, it is increasingly important to be familiar with chemotherapy for the elderly. Age-related changes in pharmacokinetics are documented for doxorubicin, etoposide, ifosfamide, daunorubicin, mitomycin, cisplatin and methotrexate. The hematological toxicity of most standard-dose chemotherapy is not affected by age in patients with normal organic functions and good performance status, although increased toxicity with aging is suggested in the use of actinomycin-D, etoposide, vinblastin, methotrexate, methyl-CCNU, doxorubicin and mitomycin, and in dose-intensive chemotherapy. Among non-hematological toxicities, only doxorubicin-induced cardiomyopathy and bleomycin-induced pulmonary toxicity are demonstrated to be accelerated in the elderly. There is no evidence that advanced age decreases the efficacy of chemotherapy for tumors, except for Hodgkin's disease and acute leukemia. These results suggest that advanced chronological age alone is not always associated with severe toxicity and poor prognosis, and that many elderly patients with cancer will benefit from chemotherapy. To answer questions regarding the optimal chemotherapy regimen, dose and intensity in this population, the influence of age should be analyzed in a multivariate approach in future studies.

Adolescent↗
PubMed1998

Characterization of a human small-cell lung cancer cell line resistant to a new water-soluble camptothecin derivative, DX-8951f.

DX-8951f, a water-soluble and non-pro-drug analogue of camptothecin, exhibits a strong inhibitory action on DNA topoisomerase I (Topo I) and in vitro cytotoxicity against various human cancer cell lines. In order to elucidate the mechanisms of its cytotoxicity, we established a DX-8951f-resistant cell line, SBC-3/DXCL1, from human small cell lung cancer cells (SBC-3) by stepwise exposure to DX-8951f. SBC-3/DXCL1 cells were approximately 400 times more resistant to DX-8951f than parent cells. The SBC-3/DXCL1 cells showed a high degree of cross-resistance to other Topo I inhibitors such as CPT-11, SN-38 and camptothecin, but not to non-Topo I targeting agents such as cisplatin, adriamycin, etoposide, and vincristine. The mechanisms of resistance of SBC-3/DXCL1 cells to DX-8951f were examined. Intracellular accumulation of DX-8951f by SBC-3 and SBC-3/DXCL1 cells did not differ significantly. Although the Topo I activity of nuclear extracts obtained from SBC-3/DXCL1 cells was the same as that of the parent cells, the Topo I of SBC-3/DXCL1 cells was resistant to the inhibitory effects of DX8951f and SN-38. Immunoblotting using anti-Topo I antibody demonstrated similar protein levels of Topo I in SBC-3 and SBC-3/DXCL1 cells. The active Topo I protein of SBC-3/DXCL1 was eluted by a high concentration of NaCl (0.4 N) compared with that of SBC-3 (0.3 N). DX-8951f stabilized the DNA-Topo I cleavable complex from SBC-3 cells, as measured by Topo I-mediated cleavage assay. In SBC-3/DXCL1 cells, DX-8951f also stabilized the DNA-Topo I complex, but with a 10-fold lower efficiency. These results suggest that a qualitative change in Topo I contributes, at least partially, to the resistance to DX-8951f in SBC-3/DXCL1 cells. Therefore, SBC-3/DXCL1 cells may have a unique mechanism of resistance to Topo I-directed antitumor drugs.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Preferential binding of E7010 to murine beta 3-tubulin and decreased beta 3-tubulin in E7010-resistant cell lines.

N-[2-[(4-Hydroxyphenyl)amino]-3-pyridyl]-4-methoxybenzenesulfonamide+ ++ (E7010) is a novel sulfonamide antimitotic agent, which is active against mouse and human tumors. E7010 binds to beta-tubulin and inhibits polymerization of microtubules. In order to clarify the mechanisms of E7010-resistance, two murine leukemic P388 subclones resistant to E7010, 0.5r-D and 4.0r-M, were characterized. The two clones showed approximately 10- and 100-fold resistance to E7010-induced growth-inhibitory effects, respectively, compared with the parental cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. These cell lines showed no cross-resistance to other anticancer agents such as taxanes, vinca alkaloids, mitomycin C, cisplatin and irinotecan hydrochloride (CPT-11). Increased alpha- and beta-tubulin protein and mRNA levels were observed in 0.5r-D and 4.0r-M cells as compared with the parental cells. We examined the isotype-specific expression of beta-tubulin in these E7010-resistant cells by a competitive reverse transcription-polymerase chain reaction method. Although a 50% increase in beta 5 isotype mRNA levels was observed in 4.0r-M cells, the levels of beta 3 isotype message in the two resistant clones were approximately 50% less than the parental cells. To elucidate the binding properties of E7010 with beta-tubulin isotypes, we prepared isotype-specific fusion proteins of beta-tubulins. Direct photoaffinity labeling of the isotype-specific fusion proteins with [14C]E7010 revealed that E7010 preferentially binds to the beta 3 isotype rather than beta 2, beta 4, and beta 5 isotype proteins. Therefore, altered expression of beta-tubulin isotypes, especially beta 3 isotype, to which E7010 binds with high affinity, may account for the decreased sensitivity of these resistant clones to E7010.

Aminophenols↗
PubMed1998

Phase III study of intensive weekly chemotherapy with recombinant human granulocyte colony-stimulating factor versus standard chemotherapy in extensive-disease small-cell lung cancer. The Japan Clinical Oncology Group.

PURPOSE: To evaluate the therapeutic significance of cisplatin, vincristine, doxorubicin, and etoposide (CODE) plus granulocyte colony-stimulating factor (G-CSF) compared with cyclophosphamide, doxorubicin, and vincristine, alternating with cisplatin and etoposide (CAV/PE) for extensive-disease (ED) small-cell lung cancer (SCLC). PATIENTS AND METHODS: Two hundred twenty-seven patients were randomized. CODE consisted of cisplatin 25 mg/m2 weekly for 9 weeks; vincristine 1 mg/m2 on weeks 1, 2, 4, and 6; and doxorubicin 40 mg/m2 and etoposide 80 mg/m2 for 3 days on weeks 1, 3, 5, 7, and 9. G-CSF 50 micrograms/m2 was administered on the days when chemotherapy was not administered. CAV/PE consisted of cyclophosphamide 800 mg/m2; doxorubicin 50 mg/m2; and vincristine 1.4 mg/m2 on day 1, which alternated every 3 weeks with cisplatin 80 mg/m2 on day 1 and etoposide 100 mg/m2 on days 1 to 3. RESULTS: Overall response rates were 77% for the CAV/PE arm and 84% for the CODE arm respectively (15% complete response in both arms). The median survival times were 10.9 months in the CAV/PE arm and 11.6 months in the CODE arm (P = .1034). The achieved dose-intensity for CODE was approximately twice that for CAV/PE for those drugs common to both arms. The incidence of leukopenia did not differ between the two arms, but anemia and thrombocytopenia had a significantly higher incidence in the CODE arm. Four treatment-related deaths from neutropenic fever occurred in the CODE arm. CONCLUSION: The CODE group had a similar median survival to the CAV/PE group. It does not appear that CODE is a useful approach to improve survival in ED SCLC.

Adult↗
PubMed1998

New chemotherapeutic agents for the treatment of non-small cell lung cancer: the Japanese experience.

Non-small cell lung cancer (NSCLC) is refractory to systemic chemotherapy, compared with small cell lung cancer. Until recently, only five drugs--cisplatin, vindesine, mitomycin, ifosfamide, and vinblastine--could produce overall response rates of 15% against NSCLC. However, recent efforts have contributed to the development of new drugs with activity against NSCLC, including irinotecan hydrochloride (CPT-11), paclitaxel, docetaxel, vinorelbine, and gemcitabine. Combination chemotherapy against NSCLC using these agents has demonstrated high response rates. In Japan, various combination chemotherapy and combined-modality regimens employing CPT-11 have been evaluated for their efficacy. Randomized controlled trials to establish new state-of-the-art treatments for NSCLC are ongoing.

Alkaloids↗
PubMed1998

[Clinical trial of IL-12 for cancer patients].

Interleukin-12 (IL-12) is a cytokine that stimulates T cells and NK cells. It induces interferon-gamma and plays a unique role in promoting type 1 T helper cell responses. In various animal models, IL-12 has shown a therapeutic effect controlling growth of primary and metastatic tumors at nontoxic doses. On the basis of these findings, IL-12 is now under clinical trial. Fever, flu-like, general fatigue, arthralgia, myalgia, leukopenia, liver dysfunction and so on are the reported toxicities of IL-12. A dramatic decrease of IL-12 AUC after consecutive dosing of IL-12, production of IL-10 and temporal elevation of NK and LAK activities after IL-12 administration have also been observed. Several patients achieve PRs after the administration, but dramatic clinical responses have never been reported. Intensive research on the mechanisms of antitumor response of IL-12 in cancer patients should be very important to the successful development of IL-12 as an anti-cancer agent.

Clinical Trials as Topic↗
PubMed1998

Overcoming drug resistance in lung cancer.

Anticancer drugs have been explored by means of random screening and demonstrated to be active against not only hematologic malignancies but also some solid tumors. Recent progress in the field of molecular biology has identified many new molecular targets for anticancer drugs. In this review, for example, signal-transduction pathways, which are influenced by newer agents like the taxanes (paclitaxel [Taxol] and docetaxel [Taxotere]) and the protein kinase C activator gnidimacrin, are evaluated. Efforts under way to integrate these new compounds into clinical trials are discussed.

Animals↗
PubMed1998

[Paclitaxel (taxol): a review of its antitumor activity and toxicity in clinical studies].

Paclitaxel (Taxol) is a new class of anti-tumor agents which act by promoting the assembly and inhibiting the disassembly of microtubules. Single-agent studies have shown its significant activity for advanced cancers in various organs including ovary, lung, breast, and head and neck. Combination therapies with other anticancer agents have been extensively investigated in these cancers. Paclitaxel combined with cisplatin is now considered to be the standard treatment for advanced ovarian cancer. In other cancers, promising results have been obtained in several studies of paclitaxel-based chemotherapy. Major toxicities of paclitaxel-monotherapy are hypersensitivity reaction, neutropenia, and peripheral neuropathy. Combination of other cytotoxic agents sometimes leads to severer toxicities such as neurotoxicity with cisplatin and cardiotoxicity with anthracycline. Although further evaluation is needed, paclitaxel will be a main agent in the treatment of advanced solid tumors.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Genetic immunotherapy by intrapleural, intraperitoneal and subcutaneous injection of IL-2 gene-modified Lewis lung carcinoma cells.

The induction and augmentation of tumor non-specific immunity and of tumor-specific immunity by intrapleural, intraperitoneal and subcutaneous injection of interleukin-2 (IL-2) gene-modified Lewis lung carcinoma (LLC) cells (LLC-IL2) was tested in C57BL/6 mice. Intrapleural injection of LLC cells induced lung tumors with a malignant effusion, intraperitoneal injection induced peritoneal tumors with ascites and subcutaneous injection induced subcutaneous tumors. Intrapleural injection of irradiated LLC-IL2 cured pre-existing lung LLC tumors and extended the survival of the mice but did not affect survival of mice with pre-existing peritoneal tumors nor did it affect the growth of s.c. tumors. Intraperitoneal injection of irradiated LLC-IL2 cured pre-existing LLC peritoneal tumors and extended the survival of the mice but did not affect survival of mice bearing lung tumors nor did it affect the growth of s.c. tumors. Subcutaneous injection of irradiated LLC-IL2 did not affect the growth of preexisting s.c. tumors and also did not improve survival of mice bearing the lung or peritoneal tumors. Injection with irradiated LLC-IL2 by all routes, i.e., intrapleural, intraperitoneal and s.c., protected against subsequent re-challenge with LLC. Eight days after the initial immunization (early stage of immunization), non-adherent mononuclear cells in the peritoneal cavity of the mice treated with intraperitoneal injection of irradiated LLC-IL2 displayed enhanced cytotoxicity against LLC, B16-F10 and P815 cells, while the cytotoxic activity of spleen cells in the same mice did not change. The efficiency of induction of tumor-specific immunity was the strongest after intraperitoneal immunization and weakest after s.c. immunization. In vitro analysis using the spleen cells of mice immunized with irradiated LLC-IL2 suggested that CD8+ T cells play a key role in tumor-specific immunity.

Animals↗
PubMed1997

cDNA cloning of a short type of multidrug resistance protein homologue, SMRP, from a human lung cancer cell line.

Members of the ATP binding cassette (ABC) superfamily are involved in the energy-dependent transport of a wide variety of substrates including anticancer agents across the membranes. We have cloned a cDNA fragment including a novel ABC sequence from a cisplatin-resistant human lung adenocarcinoma cell line, PC-14/CDDP, by reverse transcription polymerase chain reaction (RT-PCR) using degenerate primers and screened a cDNA library using the cDNA fragment as a probe. A full-length cDNA clone, BM4.8, was obtained. Sequence analysis showed that the cDNA encoded a short type of multidrug resistance protein homologue, SMRP, by computed homology search. SMRP was composed of 946 amino acids and had two ABCs with walker A and B motifs. This gene was mapped on chromosome 3 at band q27 by fluorescence in situ hybridization (FISH) analysis and was found to be expressed in various tissues by Northern blot analysis.

ATP-Binding Cassette Transporters↗
PubMed1997

Circumvention of glutathione-mediated mitomycin C resistance by a novel mitomycin C analogue, KW-2149.

A novel antitumor antibiotic 7-N-[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl] mitomycin C (KW-2149), an analogue of mitomycin C (MMC), is activated by thiol molecules, such as glutathione (GSH). To clarify the relationship between cellular GSH levels and the cytotoxicity of KW-2149, a murine fibroblast cell line (NIH/3T3) was transfected with human gamma-glutamylcysteine synthetase (gamma-GCS) cDNA, which codes a rate-limiting enzyme of GSH synthesis. Transfected cells (3T3/GCS) displayed increased gamma-GCS mRNA levels, gamma-GCS activity and GSH content, compared with NIH/3T3 cells. 3T3/GCS cells exhibited a 4.4-fold resistance to MMC, but not to KW-2149 (x 0.69), using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, suggesting that the increased cellular GSH levels did not affect the growth-inhibitory effect of KW-2149. KW-2149 exerted a greater growth-inhibitory effect than MMC on cisplatin- and doxorubicin-resistant cells with cross-resistance to MMC. KW-2149 exhibited a greater growth inhibitory effect than MMC not only on cells with GSH-mediated MMC resistance but also on cells with acquired resistance. We thus conclude that KW-2149 might be a clinically useful drug.

3T3 Cells↗