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Biomedical subjects

T Ohnuma

Publications and source records attributed to T Ohnuma.

At least 73 records · Page 4Linked to original sources
PubMed1991

BOMM regimen for the treatment of advanced head and neck carcinoma.

Eighty patients with Stage III and IV head and neck cancer were treated with a four-drug regimen consisting of bleomycin, vincristine, methotrexate, and mitomycin-C (BOMM regimen). Of 69 patients evaluable for response, 7 complete and 40 partial responses were achieved, with an overall response rate of 68%. The median duration of response was 13 weeks (range 3-41 weeks). Anorexia, lassitude, febrile reactions, and myelosuppression were major side effects. The BOMM regimen produced a response rate significantly better than VCR, BLM, and MTx combination (VBM) which we previously reported with improved response duration. This study demonstrates that the BOMM regimen, which can be administered on an outpatient basis, achieved a response rate comparable to cisplatin-containing regimens. The BOMM regimen may be beneficial to patients with poor general condition and/or marginal renal dysfunction who are in high risk of toxicity-associated cisplatin-containing regimens.

Adult↗
PubMed1990

Inhibition of invasion of invasive human bladder carcinoma cells by protein kinase C inhibitor staurosporine.

To study the effect of the protein kinase C (PKC) inhibitor staurosporine on invasion, we selected the invasive human bladder carcinoma cell line EJ. Total PKC activity was more than twofold higher in the EJ cells than in RT4 cells (superficial human bladder carcinoma cells), which do not pass through an artificial basement membrane. There was more PKC activity in the cytosol than in the membrane of EJ cells. Staurosporine, at nontoxic concentrations, inhibited the invasion of EJ cells through an artificial basement membrane in a dose-dependent manner. Staurosporine caused a dose-dependent inhibition of cell motility but did not inhibit cell attachment. Staurosporine represents a new agent for the inhibition of tumor cell invasion and may prove useful in studying the mechanisms responsible for this phenomenon.

Alkaloids↗
PubMed1990

Hypersensitivity reactions from taxol.

Taxol is an antitumor agent in clinical trial that has been shown to have activity against advanced ovarian carcinoma and melanoma. Hypersensitivity reactions (HSRs) have been one of the toxicities observed with administration of this drug. Of 301 patients treated, 32 patients have had definite (27 patients) or possible (five patients) hypersensitivity reactions to taxol. All but one patient had the reaction from the first or second exposure to this agent. Reactions occurred at a variety of doses and were characterized most frequently by dyspnea, hypotension, bronchospasm, urticaria, and erythematous rashes. Thirteen (41%) patients had received premedication designed to prevent such toxicity; nevertheless, they sustained HSRs. Prolonging the drug infusion appears to have somewhat reduced, but not obviated, the risk of HSRs. The cause (taxol itself or its excipient Cremophor EL; Badische Anilin und Soda-Fabrik AG [BASF], Ludwigshafen, Federal Republic of Germany) and the mechanism of these reactions to taxol are unknown. We provide guidelines to prevent or minimize such toxicity and treat reactions if they still occur.

Adult↗
PubMed1990

[Combination of chemotherapy and immunotherapy in man--review].

Such biological response modifiers (BRMs) as interferon, interleukin-2 and tumor necrosis factor were shown to have some antitumor activity in man. In addition, preclinical studies have demonstrated favorable interactions of these BRMs and chemotherapeutic agents. Animal studies have shown cure in certain combinations. Therefore, it has become important to study whether combinations of these BRMs and chemotherapeutic agents would increase response rate, survival and/or the quality of life in patients with cancer. In this review entire articles on this subject published in English literature were evaluated to assess current status. While there were isolated articles describing improved response rates, a majority of articles failed to document clinical benefit from the combinations. Some articles recorded increased toxicity without therapeutic benefit. At this time there was only one published phase III study comparing chemotherapy and the chemotherapy combined with BRM, in this case interferon: response rate and survival were identical in the two groups. The review of these articles resulted in identification of several factors considered to be associated with the discrepancy between preclinical data vs. clinical results: larger tumor load in man as compared to animals, importance of pharmacokinetic barrier which can not be incorporated in in vitro systems, differences in dosing schedules between animals and man, and differences in assessing response. Presence of negative preclinical data can not also be ignored. It is concluded that in order for better assessment of this modality of treatment further phase III studies are needed. Therapeutic effects may improve if dose scheduling are optimized and patients with small tumor load are studied preferentially.

Antineoplastic Agents↗
PubMed1990

Schedule-dependent interaction of cytarabine plus doxorubicin or cytarabine plus mitoxantrone in acute myelocytic leukemia cells in culture.

Schedule-dependent interaction of 1-beta-D-arabinofuranosylcytosine (ara-C, cytarabine) plus doxorubicin or ara-C plus mitoxantrone was studied in vitro using HL-60 human acute myelocytic leukemia cell line. The cells were exposed for 1 hr to each drug simultaneously, or sequentially (up to a 28-hr interval), and cell kill effects were determined by clonogenic assay. The results were compared with controls in which cells were exposed to the individual drug only and seeded after appropriate intervals. Simultaneous exposure to two drugs produced lethal effects, but no more than those produced by doxorubicin or mitoxantrone alone. Ara-C followed by doxorubicin produced time-dependent increases in cell kill that was parallel to the doxorubicin alone control, indicative of no true potentiation. In contrast, ara-C followed by mitoxantrone produced striking increases in cell kill effects. Thus, ara-C followed by mitoxantrone resulted in more than 10-fold increases in cell kill at the intervals of greater than or equal to 8 hr between exposures, and the strong cell kill effects were maintained. Our data indicate that: (a) simultaneous exposure to ara-C and doxorubicin or mitoxantrone is less than additive; (b) ara-C followed by doxorubicin is probably only additive; and (c) ara-C followed by mitoxantrone is more than additive, and cell kill effects are sustained.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Relationship between the in vitro colony growth of human tumors and cytologic diagnosis.

The cytologic examinations and cloning efficiencies of 47 human tumor specimens (19 ovarian carcinomas, 6 sarcomas, 5 lung carcinomas, and 17 miscellaneous tumors) were compared to evaluate the predictability of clonogenecity by cytologic diagnosis. Cytologic examination preceding clonogenic assay identified the 50% to 60% of all specimens that failed to yield in vitro chemotherapy sensitivity by this assay, with a false-negative rate of 10%. The frequency of cytologically identifiable tumor cells in the plating suspension was independent of the histologic type of tumor (ovarian carcinoma or others) and the nature of the specimen (solid tumor or malignant effusion). Nearly 66% of all specimens were cytologically negative. The in vitro sensitivity can be assessed in approximately 75% of cytologically positive specimens. Cytologic evaluation preceding soft-agar clonogenic assay of human tumors can reduce cost and effort by predicting colony-producing specimens.

Cell Survival↗
PubMed1989

Multidrug resistance in a human leukemic cell line selected for resistance to trimetrexate.

Trimetrexate (TMQ) is a lipophilic antifolate shown to have antitumor activity in humans. TMQ-resistant sublines of the MOLT-3 human acute lymphoblastic leukemia cell line were developed and were designated as MOLT-3/TMQ200, MOLT-3/TMQ800, and MOLT-3/TMQ2500 based on degrees of resistance to TMQ. The TMQ resistance was accompanied by 5- to 7-fold increases in dihydrofolate reductase activity and markedly reduced cellular TMQ accumulation. Methotrexate accumulation was not impaired in TMQ-resistant cells. TMQ retention (efflux) was unchanged in these TMQ-resistant cells. Verapamil enhanced the TMQ accumulation in the resistant cells to the level seen in the parent cells but had no effects on the TMQ retention. These sublines were cross-resistant not only to methotrexate but also to vincristine, doxorubicin, daunorubicin, and mitoxantrone. There was no cross-resistance to bleomycin or cisplatin. Resistance to vincristine, doxorubicin, daunorubicin, and mitoxantrone was reversed by verapamil. TMQ resistance was only minimally reversed by verapamil and methotrexate resistance not affected at all. Both cellular accumulation and retention of vincristine and daunorubicin in the TMQ-resistant cells were markedly decreased. Verapamil enhanced both accumulation and retention of the drug. Plasma membrane fractions of the TMQ-resistant cells analyzed by urea-sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by staining with Coomassie Blue revealed the presence of a distinct band with a molecular weight of 170,000. Immunoblot analysis with 125I-labeled monoclonal antibody raised against P-glycoprotein of multidrug-resistant Chinese hamster ovary cells (C219) cross-reacted with the Mr 170,000 protein of the TMQ-resistant cells. These results show that the TMQ-resistant cells displayed not only decreased TMQ uptake and increased dihydrofolate reductase but also characteristics associated with a classical multidrug-resistant phenotype. Multidrug resistance includes lipophilic antifolate.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Effects of simultaneous and sequential exposure to granulocytic and monocytic inducers on the choice of differentiation pathway in HL-60 promyelocytic leukemia cells.

HL-60 promyelocytic leukemic cells were induced to differentiate by the combination of two alternative inducers: phorbol-12-myristate 13-acetate (PMA) and either dimethyl sulfoxide (DMSO) or retinoic acid (RA). Simultaneous exposure to optimal concentrations of PMA and either DMSO or RA potentiated PMA-induced differentiation into monocyte-macrophages. Granulocytic inducers combined with lower concentration of PMA competed with the latter for the differentiation pathway, producing monocyte-macrophages, granulocytes, paramyeloid and giant multinucleated cells. Lineage specificity of cells treated sequentially with two discrete exposures to alternative inducers depended on the order of exposure. The first exposure initiated differentiation into the pathway specific for the inducer used. The second exposure determined lineage specificity and stimulated terminal differentiation. Thus, treatment with RA for 24-72 h followed by PMA resulted in monocyte-macrophage differentiation; reversed order of exposure resulted in granulocytic differentiation. The switch in the differentiation pathway occurred at the relatively advanced stages of differentiation.

Cell Differentiation↗
PubMed1989

Effects of physiological oxygen environment on drug-induced cell lethality of multicellular tumor spheroids from human lung cancer.

Advanced malignant tumors of certain histological types contain a hypoxic and necrotic core. Multicellular tumor spheroids (MTS) have the characteristics of chronically hypoxic cells in the center. We studied the effects of physiological oxygen environment on MTS growth and the cell lethality produced by doxorubicin (DXR) and cisplatin (DDP). MTS were made from 2 human lung cancer cell lines; PC-6 small cell and PC-10 squamous cell carcinoma, and grown for 2, 3 or 4 weeks; either in 5% CO2/air or 5% 02/5% CO2/90% N2. They were exposed to graded concentrations of DXR for 1 hr and cell lethality was determined by clonogenic assay. In the physiological oxygen environment MTS growth was retarded for both cell lines. PC-6 MTS grown in physiological oxygen environment were more sensitive to DXR than those developed in air. The differential sensitivity was most pronounced with the 2 week old MTS and gradually narrowed with increasing MTS size. In contrast, PC-10 MTS developed in the physiological oxygen environment were more resistant to DXR than those in air; the differences were again most pronounced in 2 week old MTS. There were little differences in cell kill effects of DDP, irrespective of cells being in monolayer or in MTS and growing in air or in physiological oxygen environment. These observations are consistent with the interpretation that cells in PC-6 MTS are scarcely affected by the physiological oxygen environment but easily affected by DXR, whereas cells in PC-10 MTS responded vice versa.

Antineoplastic Agents↗
PubMed1988

Simultaneous soft agar cloning of ascites and solid tumor specimens from patients with ovarian cancer.

Concurrent Cloning Efficiencies (CE) of both ascites and solid tumor samples from 36 patients with ovarian carcinoma were studied using the soft agar assay. The CE of both were highly variable (range, 0-1.234% and 0-0.802%, respectively). There was marked intrapatient and interpatient heterogeneity in the CE. Of the 36 tested, comparative CE were evaluable in 29. CE was 0 in both solid tumor and ascites in one patient. CE was 0 in four other ascites samples from four patients. In other 24, the relative CE of solid tumor/ascites from each patient ranged from 0.066 to 435. In the 29 patients with samples of ascites and a solid tumor evaluable for concurrent CE, the median colony counts of solid tumors was more than tenfold higher than ascites. The solid tumors obtained from 31 patients had a significantly higher CE than tumor cells obtained from ascites samples from 32 patients. Solid tumors were significantly better than ascites for in vitro testing based on the data that 75% (27/36) of solid tumors and only 31% (11/36) of ascites formed greater than or equal to 30 colonies. The drug sensitivity profiles of tumor cells from a solid tumor and ascites of the same patient appear similar. Based on these observations, it may be more cost and labor effective to do soft agar in vitro chemotherapy assays using a solid tumor than ascites in ovarian carcinoma.

Agar↗
PubMed1988

Effects of vincristine in combination with methotrexate and other antitumor agents in human acute lymphoblastic leukemia cells in culture.

The effects of vincristine (VCR) in combination with methotrexate (MTX) and other antitumor agents were evaluated by cell growth inhibition assay using a human acute lymphoblastic leukemia cell line (MOLT-3). The data were analyzed with the aid of an isobologram using the concept of an envelope of additivity (G. G. Steel and M. J. Peckman, Int. J. Radiat. Oncol., 5:85-91, 1979). Simultaneous exposure of VCR and MTX produced subadditive or mutually protective interactions. Sequential exposure to VCR first followed immediately by MTX produced similar interactions. When the interval of VCR exposure first and then MTX was increased from 0 to 3, 8, and 24 h, the inhibition of cell growth moved from protection and subadditivity to additivity only. The reversed order of exposure to the 2 drugs produced an entirely different picture. Thus, when the interval of MTX exposure first followed by VCR increased from 0 to 3, 8, and 24 h, the inhibitory effects of the combination changed progressively from the area of subadditivity to the area of supraadditivity. When these data were evaluated using median effect plot analyses (T-C. Chou and P. Talalay. In: New Avenues in Developmental Cancer Chemotherapy, pp. 36-64. Orlando, FL: Academic Press, 1987), strongly synergistic interaction of this sequence at space intervals was confirmed. These data show that the synergistic effects were produced only when MTX was followed 8 or 24 h later by VCR. Other schedules were only additive or even antagonistic. Simultaneous exposure of VCR with daunorubicin, 1-beta-D-arabinofuranosylcytosine, or bleomycin also had subadditive and protective effects. VCR, followed by daunorubicin with the interval of 24 h and vice versa, was again subadditive and protective. VCR, followed by 1-beta-D-arabinofuranosylcytosine with the interval of 24 h and vice versa, was again subadditive or additive only. Simultaneous and continuous exposures of VCR with vinblastine or L-asparaginase were only marginally supraadditive.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Effects of cisplatin plus fluorouracil vs cisplatin plus cytarabine on head and neck squamous multicellular tumor spheroids.

We compared the efficacy of cisplatin plus fluorouracil vs cisplatin plus cytarabine against HEp-2 head and neck carcinoma cells in monolayer and multicellular tumor spheroid (MTS) systems. Increases in exposure time to cisplatin and fluorouracil from one to 24 hours resulted in approximately tenfold and 1000-fold increases, respectively, in cell lethality for both monolayer and MTS cells. Dose-response curves for cisplatin or fluorouracil on MTS cells closely followed those from monolayer cells, indicating good drug penetration into the MTS core. In contrast, dose-response curves on MTS cells after 24-hour exposure to cisplatin and cytarabine showed progressively lesser efficacy at higher drug concentrations. For monolayer cells, cisplatin plus fluorouracil and cisplatin plus cytarabine were both synergistic, the latter combination more synergistic than the former. For MTS cells, both combinations again showed synergistic interaction at moderate to high effect levels. Heightened synergistic interaction was demonstrated especially with the cisplatin plus cytarabine combination. Thus, the cisplatin plus cytarabine combination was always more synergistic than cisplatin plus fluorouracil. These data may serve as a basis for additional clinical trials of cisplatin plus cytarabine in the treatment of patients with head and neck carcinoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Interactions of doxorubicin and cis-platin in squamous carcinoma cells in culture.

Doxorubicin (DXR) has a positive inoculum effect and penetrates poorly into the core of multicellular tumour spheroids (MTS). Cis-platin (DDP) displays neither of these characteristics. We evaluated whether combining these 2 agents would influence the cell kill effect at a tumour mass level. MTS were produced from a PC-10 squamous lung carcinoma cell line. MTS were exposed to either drug first for 1 h with different intervals between exposure. Cells were then trypsinized to a single cell suspension and subjected to clonogenic assay. Combination effects were analyzed by median effect plot analysis. The more MTS ml-1 medium, the lower the cell kill effect of DXR. Simultaneous exposure to the 2 drugs was synergistic. DXR exposure first followed by DDP was less efficacious than, or the same as, the simultaneous exposure. In contrast, DDP followed by DXR was more efficacious with the best cell kill at a 1 h interval between each drug. This phenomenon was observed even at non-toxic doses of DDP. The fluorescent microscopic study of DXR indicated that prior exposure of MTS to DDP resulted in increased DXR penetration into the MTS core leading to heightened synergism with this sequence. These data suggest that the proper combination of DXR plus DDP should be in sequence with DDP first. Clinical, toxicological and pharmacological trials of DDP administration first, followed by DXR, are warranted.

Carcinoma, Squamous Cell↗
PubMed1988

Simultaneous flow cytometric detection of nuclear DNA and tumor-associated antigens in lung cancers.

Flow cytometric (FCM) determinations of DNA index were found to be insufficient to distinguish the presence of tumor cells from normal ones in neoplastic tissues obtained from 29 patients with lung cancer. Therefore, the DNA and tumor-associated antigen (TAA) contents of cultured human lung cancer cells were simultaneously analyzed using FCM to assess whether this dual technique would help in distinguishing tumor cells from normal ones. For the study, cells from PC-10 (a squamous cell carcinoma line), PC-3 (an adenocarcinoma line) and PC-6 (a small cell carcinoma line) were mixed with normal peripheral lymphocytes. The TAAs studied were carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCCA) and neuron-specific enolase (NSE). The alcohol-fixed cells were treated with the respective primary TAA, followed by fluorescein-isothiocyanate-conjugated secondary antibody; the cellular DNA was then stained using propidium iodide. Red and green fluorescences were measured simultaneously by FCM. The results showed CEA mainly in PC-3 cells, SCC in PC-10 cells and NSE in PC-6 cells; thus, each cell type had a relatively specific TAA. DNA content and cell size analyses differentiated neoplastic cells from normal lymphocytes for PC-3 and PC-10 cells, but not for PC-6 cells. Simultaneous FCM analyses of DNA and the TAA specific for the individual cell type made it possible to distinguish all tumor cell types from normal lymphocytes.

Adenocarcinoma↗