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At least 973 records · Page 54Linked to original sources
PubMed1986

Interference of target cell catalase with an early step of the neutrophil cytolytic pathway.

The hypochlorous acid (HOCL)-dependent lysis of human red blood cells (HRBC) targets by neutrophils, activated with opsonized zymosan particles (OPZ), was increased by inhibiting HRBC catalatic activity with aminotriazole (AT; HRBCAT). The inhibition of HRBC glutathione cycle activity with carmustine (BCNU; HRBCBCNU) had no effect. In addition, the recovery of hydrogen peroxide (H2O2) and HOCL from neutrophils, activated under conditions similar to those used for cytotoxicity assay, was reduced by the presence of HRBC and restored by replacing HRBC with HRBCAT, but not with HRBCBCNU. Linear relationships were found between the increments in the neutrophil-mediated lysis, observed by using HRBCAT instead of HRBC, and the increments in the H2O2 or HOCL recovery, detected by replacing HRBC with HRBCAT. Together these data, coupled with the results obtained by probing neutrophil cytolysis with chemical agents, suggest that the increased cytolytic efficiency displayed by neutrophils against HRBCAT, inhibited in their catalatic activity, is due to an enhanced availability of neutrophil-derived H2O2, with a consequent enhancement in the HOCL production (according to the following reaction: (formula; see text). Thus it appears that HRBC catalase restrains the neutrophil cytolytic activity, by interfering with an early step of the pathway through which neutrophils generate cytotoxins.

Amitrole↗
PubMed1986

Combined alkylators and multiple-site irradiation for extensive small cell lung cancer: a Southwest Oncology Group Study.

The Southwest Oncology Group performed a study for patients with extensive small cell lung cancer in which two hypotheses were tested: that combined alkylating agents for induction might improve the initial response rate; and that multiple-site, involved-field consolidation with irradiation in patients with response to chemotherapy might further improve response quality and duration. A regimen of combined alkylating agents plus vincristine [carmustine, thiotepa, vincristine, and cyclophosphamide (BTOC)] was compared to our standard program of cyclophosphamide, doxorubicin, and vincristine (CAV). Patients with bone marrow metastases and/or disseminated bone metastases were randomized to BTOC or CAV as initial induction therapy, but received no multiple-field irradiation afterward. Among 189 such patients, the overall response rates were similar (48% to BTOC and 61% to CAV, with complete remission in 5% and 15%, respectively). Toxic effects were also comparative, with 23% sustaining life-threatening or fatal complications on BTOC and 16% on CAV. Median survival (5.9 and 7 months for BTOC and CAV, respectively) and overall survival were not different, and are superimposable upon our previously reported results with CAV alone. For patients with no evidence of bone marrow involvement and no metastases identified beyond the confines of ipsilateral hemithorax, liver, and brain, the plan of therapy consisted of induction chemotherapy (BTOC or CAV) every 3 weeks for three cycles, followed by multiple-field irradiation consolidation to sites of prior involvement. Among 239 such patients, response rates to therapy initiated with BTOC and CAV were also similar: 54% for BTOC and 62% for CAV, with complete response in 16% and 13%, respectively. However, the program of BTOC followed by multiple-site irradiation was associated with a higher incidence of severe or life-threatening thrombocytopenia (23% versus 8% for CAV), accounted for almost entirely by patients receiving hepatic irradiation after chemotherapy, among whom the incidence of this complication (grade 3 or 4) was 76% and 14%, respectively. Other toxic effects, including granulocytopenia, were comparable. With the exception of thrombocytopenia in the cited subgroup, multiple-field irradiation consolidation proved feasible and tolerable, with improved quality of response evident after its initiation in 24% of 135 patients. However, a similar proportion developed disease progression during or shortly after radiation therapy, and the median survival of patients who received irradiation was only 9 months (7 months from the start of consolidation).(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Autologous bone marrow transplantation in the treatment of malignant lymphoma and Hodgkin's disease.

High-dose chemotherapy, both with and without radiotherapy, was pioneered in the treatment of acute leukemia in relapse with allogeneic transplantation, exploiting the steep dose-response curve characteristic of some hematologic neoplasms. Extension to the malignant lymphomas was strengthened by early success in Burkitt's lymphoma and in syngeneic transplantation for lymphoma. The optimal regimen (BACT [carmustine, cytarabine, cyclophosphamide, 6-thioguanine]) and setting are still under investigation for the various grades of lymphomas. The early published experience demonstrated a low ultimate "cure" rate when transplantation was performed in advanced, bulky, and refractory disease. A survey of published reports up to 1986 showed only 16 of 112 long-term, disease-free survivors when autologous bone marrow transplantation (ABMT) was performed in refractory relapse as opposed to 33 of 53 for patients transplanted in second or subsequent remission or in first partial remission. Refractoriness to conventional-dose chemotherapy (no response or progressive disease) cannot be salvaged in the majority of cases. Bone marrow involvement complicates the use of ABMT and may require in vitro elimination with monoclonal antibodies/complement or cytotoxic chemicals. The Dana-Farber Cancer Institute experience shows that the former in vitro treatment does not inhibit bone marrow grafting. When selection criteria for ABMT are applied in drug-sensitive relapse, 50% to 60% long-term, disease-free survival may be expected. Definition of poor prognostic factors in large cell lymphoma may identify patients for ABMT as consolidation of first remission. The issue of marrow purging is unsettled at the present time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Survey of the effect of adding Fluosol-DA 20%/O2 to treatment with various chemotherapeutic agents.

The tumor growth delays (TGDs) observed with a series of antineoplastic agents with or without Fluosol-DA and carbogen breathing (95% oxygen, 5% carbon dioxide) in the FSaIIC fibrosarcoma are shown. All but two of eleven alkylating agents examined showed some degree of positive effect by the addition of Fluosol-DA and carbogen breathing to drug treatment. The largest effects were seen with busulfan and procarbazine. Melphalan and the nitrosoureas, carmustine, lomustine, semustine, and chlorozotocin, gave increases in TGD ranging from 2- to 6-fold with the addition of Fluosol-DA and carbogen breathing. Modest increases were seen with cytoxan and dacarbazine. Cisplatin showed no additional TGD with Fluosol-DA and carbogen breathing, and mitomycin showed a negative effect. The addition of Fluosol-DA and carbogen breathing to bleomycin treatment increased the TGD produced by 5- to 6-fold compared to the drug alone. With vincristine and etoposide at three different doses, TGDs increased 2.4- to 3-fold in combination with Fluosol-DA and carbogen breathing. Increases of 1.3- to 1.4-fold in the TGD were observed with methotrexate and 5-fluorouracil with Fluosol-DA and carbogen breathing. Adding Fluosol-DA and carbogen breathing to treatment with several of the drugs examined resulted in significant enhancement of TGD and therefore may lead to an improved therapeutic outcome when added to certain currently used clinical regimens.

Alkylating Agents↗
PubMed1988

Cytolysis mediated by phagocytosing neutrophils. Influence of the presence of an alternative target cell population.

When added to the hypochlorous acid (HOCl)-dependent cytolytic system constituted of opsonized zymosan (OPZ)-triggered neutrophils and chicken erythrocyte (CRBC) targets, human erythrocytes (HRBCs) inhibited the lysis. The replacement of HRBCs with cells pretreated with amino-triazole (AT) to inactivate catalase prevented the HRBC inhibitory effect almost completely. HRBCs, pretreated with carmustine (BCNU) to inhibit glutathione cycle activity, behaved as untreated cells. Thus, HRBCs appear to protect CRBCs via an AT-inhibitable, i.e. catalase-dependent, process. When measured under conditions similar to those used for the lytic assay, both the hydrogen peroxide (H2O2) and the HOCl recovery from the neutrophil-CRBC system was reduced by HRBCs and restored by pulsing HRBCs with AT but not BCNU. The results suggest that HRBC catalase rescues CRBCs from neutrophil-delivered attack by "stealing" H2O2 from the neutrophil HOCl-generating myeloperoxidase (MPO)-H2O2 system.

Animals↗
PubMed1986

Sensitivity of proliferating cultured murine pancreatic tumor cells to selected antitumor agents.

Cultured cell populations derived from the refractory murine pancreatic ductal adenocarcinoma (Panc 02) were propagated in modified Eagle's minimal essential medium supplemented with 20% fetal bovine serum and had a doubling time of 19.1 +/- 4.7 hours (mean +/- SD). The Panc 02 cell populations were tested against 8 antitumor agents and exhibited different sensitivities to the agents in a 24-hour growth-inhibition assay. The concentration that inhibits the growth of the test culture by 50% relative to the growth of the control culture (IC50) in micromolars was determined for each agent. The IC50 values were: doxorubicin (ADR), 0.055; vincristine (VCR), 0.042; 5-fluorouracil, 1.92; cytarabine, 5.35; melphalan, 10.5; cisplatin, 17.0; carmustine (BCNU), 46.2; and lomustine (CCNU), 52.6. These IC50's were estimated to be pharmacologically attainable concentrations in mice. On a micromolar basis, the Panc 02 cells were the most sensitive to VCR and ADR and the least sensitive to BCNU and CCNU. By the use of a colony-forming assay and a 24-hour exposure period and the evaluation of each agent at 1/3 X IC50, 1 X IC50, and 3 X IC50, the degree of cell killing was greater than predicted on the basis of the IC50's determined in the growth-inhibition assay. The use of a 1-hour exposure period resulted in a very minimal reduction in viability of the cell populations except for BCNU and CCNU. It was concluded that the degree of cell killing was a function of drug concentration and time of exposure and that the pancreatic tumor in vivo should be sensitive to these agents, provided effective concentrations and exposure periods can be achieved at the tumor target sites.

Animals↗
PubMed1986

Limitations of urinary mutagen assays for monitoring occupational exposure to antineoplastic drugs.

The sensitivity of the Salmonella reversion test of Ames as a screen for accidental absorption of 17 antineoplastic agents by drug handlers was evaluated. Dilutions of each drug were added to agar inoculated with each of two Salmonella typhimurium strains (TA98 and TA100); control plates contained no test drug. Colonies were counted after incubation at 36 degrees C for 48 hours. The drugs were tested in the presence of a liver preparation to provide metabolic activation of mutagenicity. Urine samples collected from patients after doses of three mutagenic drugs were extracted and tested with the Ames test. For 11 of the 17 drug solutions, no mutagenic activity was seen, but many of these 11 were toxic to the organisms. The most highly mutagenic drugs were doxorubicin and cisplatin, with mechlorethamine, carmustine, dacarbazine, and cyclophosphamide exhibiting less mutagenic activity. Urine from patients treated with doxorubicin or cyclophosphamide showed mutagenicity, but the results suggested that the quantity of these drugs that would have to be absorbed to produce a definite reaction in urine is unlikely to be achieved by drug handlers who use standard precautions. Because of its lack of sensitivity and the potential effects of environmental and dietary factors on the results, this bacterial mutagenicity test should not be used routinely for detection of accidental absorption of antineoplastic drugs.

Antineoplastic Agents↗
PubMed1986

Cytarabine and cisplatin in advanced malignant melanoma.

Twenty-seven consecutive patients with advanced malignant melanoma were treated with cytarabine (Ara-C) and cisplatin. Of 25 evaluable patients, four achieved partial response, for a median duration of 3 months. Three of four responders belonged to the group of seven patients given Ara-C at a dose of 3 g/m2. The predominant toxic effect was hematologic and related to the dose of Ara-C. The cost-benefit ratio of this combination is inferior to that of dacarbazine or carmustine alone.

Aged↗
PubMed1987

Lack of enhanced myelotoxicity with buthionine sulfoximine and sulfhydryl-dependent anticancer agents in mice.

The lethal and non-lethal effects of L-buthionine-SR-Sulfoximine (BSO) with the sulfhydryl-dependent anticancer agents (SHDAA) were investigated in mice. The agents studied included carmustine (BCNU), cyclophosphamide (CTX), doxorubicin (DOX) and melphalan (LPAM). It was shown in normal mice that BSO is nontoxic when given IP or PO at a dose 5 g/kg. In pharmacodynamic studies with two different doses of BSO in CD-1 mice, the liver, kidney and heart demonstrated diurnal variations in thiol content and dose-dependent depression of tissue non-protein sulfhydryl (NPSH) levels. In acute lethal survival studies, mice treated with CTX and BSO exhibited increased lethality with seizures as a possible cause of death. This effect was not seen with BCNU, DOX and LPAM. Evaluations of organ-specific biochemical markers, showed slight elevations in LDH enzyme levels while bone marrow suppression was not enhanced using both in vivo spleen colony assay and in vitro colony forming unit myelotoxicity assays. These results show that the addition of BSO with SHDAA enhances the acute lethality of some agents such as CTX, and may also increase the non-myelosuppressive toxicities of other agents. It is recommended that BSO be used with caution in combination with SHDAA and that monitoring of hepatic enzymes be routinely performed.

Animals↗
PubMed1985

NMU-1, a new transplantable mouse lung tumor: biological and chemosensitivity properties in vivo.

NMU-1 is a lung adenocarcinoma induced by N-nitroso-N-methyl-urea in a BALB/c Lac Dp mouse and maintained in vivo by sc passages of tumor fragments. No spontaneous regressions have been observed. After sc implantation, NMU-1 metastasizes to the lung as shown by a bioassay. Seven established antitumoral drugs were used to evaluate the chemosensitivity of this neoplasm. Mitomycin, cyclophosphamide, and cisplatin statistically affected tumor growth, as evaluated by three end points (ie, tumor weight, increase in lifespan, and tumor growth delay). 5-FU, doxorubicin, and vincristine showed significant activity on two end points. Carmustine did not affect any end points.

Adenocarcinoma↗
PubMed1985

Inhibition of DNA ligase from human thymocytes and normal or leukemic lymphocytes by antileukemic drugs.

Human DNA ligase was purified from both normal and leukemic peripheral lymphocytes and normal thymocytes. The activity of the purified enzymes was assayed in the presence of several widely used antileukemic drugs. Melphalan and prednisone at 5 mM had no effect. Carmustine, chlorambucil, and cyclophosphamide were more effective at inhibiting the enzyme from leukemic cells, whereas Adriamycin and vinblastine and their derivatives were stronger inhibitors of the enzyme from normal cells. Vincristine and etoposide inhibited DNA ligase from thymocytes and normal lymphocytes with a low Ki but were totally ineffective on the enzyme from leukemic cells. The three classes of intercalating anthracyclines, Vicia alkaloids, and podophyllotoxin derivatives, were the only drugs found to markedly inhibit DNA ligases from normal cells. Less substituted molecules of the Vicia alkaloids and podophyllotoxin classes were the more active inhibitors, whereas in the intercalating anthracycline group, it was the more substituted compounds. The clinical consequences of these observations are discussed with respect to the role of DNA ligase in DNA replication and repair.

Antineoplastic Agents↗
PubMed1985

Multidrug (pleiotropic) resistance in doxorubicin-selected variants of the human sarcoma cell line MES-SA.

The emergence of drug-resistant tumor cells is a major limiting factor in cancer chemotherapy. There is little information about the nature of such resistant variants among human cancer cell populations. Doxorubicin (DOX)-resistant sublines of the human sarcoma cell line MES-SA were selected by continuous in vitro exposure to DOX. Stepwise increases in DOX concentration produced variants which were 25- and 100-fold resistant to DOX. These sublines displayed marked cross-resistance to daunorubicin, dactinomycin, mitoxantrone, colchicine, vincristine, vinblastine, and etoposide and moderate resistance to mitomycin C and melphalan. Cross-resistance was not observed, however, to methotrexate, 5-fluorouracil, bleomycin, carmustine, or cisplatin. DOX resistance in these cell lines appeared to be stable despite long periods of growth in drug-free medium. Two additional marker chromosomes were identified in the 100-fold resistant variant, which indicated clonal selection during drug exposure, but no double minute chromosomes or homogeneously staining regions were noted. Doxorubicin accumulation in the DOX-resistant cells was reduced by approximately 50% compared to that of the sensitive MES-SA cells, as a result of enhanced efflux of DOX from the resistant cells. There was no evidence of appreciable DOX metabolism by either the sensitive or resistant cells. These studies demonstrate marked DOX resistance and multidrug resistance arising in a human sarcoma line during exposure to DOX. The pleiotropic nature of this resistance is similar to that described in other models. Decreased drug accumulation due to enhanced drug efflux is identified as a major mechanism of resistance in these cells, although other factors may also be involved.

Carbon Radioisotopes↗
PubMed1978

Unmaintained remissions in multiple myeloma.

Twenty-eight patients with multiple myeloma responding to prior melphalan-prednisone combinations, but without additional chemotherapy, were followed until relapse. Patients receiving no further treatment had a median survival time similar to that of those receiving indefinite courses of melphalan-prednisone or carmustine-prednisone. Prolonged periods of unmaintained remission occurred primarily in patients without extensive disease at the time of diagnosis or in whom the abnormal protein disappeared from the electrophoresis strip. The initial relapse after an unmaintained remission was controlled in 80% of patients with the resumption of melphalan-prednisone, but second remissions were usually less marked in degree and shorter in duration. Results supported the long-term evaluation without chemotherapy of selected patients with low numbers of plasma cells after treatment who were likely to experience long durations of disease stability and respond again to retreatment with melphalan-prednisone.

Cell Transformation, Neoplastic↗
PubMed1984

Cytotoxicity of several chemotherapeutic agents in a human pancreatic cancer cell line (Colo-357).

Seven commonly available chemotherapeutic drugs were used to determine the concentration and time of exposure necessary to kill the newly available human pancreatic cancer cell line, Colo-357. The exposure periods were 2, 6, 12, and 24 hours. The most active drugs were methotrexate, mitomycin, and doxorubicin, each with an ID50 less than 0.1 microM for both a 12- and a 24-hour exposure. Cisplatin was intermediate, with an ID50 of approximately 0.7 microM at 12 and 24 hours. 5-FU, carmustine, and streptozocin were the least effective agents, with ID50 values greater than 50 microM after a 12-hour exposure and greater than 25 microM after a 24-hour exposure.

Antineoplastic Agents↗
PubMed1984

Treatment of human glioma and medulloblastoma tumor lines in athymic mice with diaziquone and diaziquone-based drug combinations.

We used diaziquone (NSC 182986) alone and in combination with other antineoplastic drugs to treat six human glioma and one human medulloblastoma tumor lines growing s.c. in athymic mice. Pharmacokinetic studies of diaziquone in the plasma of athymic mice indicated rapid clearance with a half-life of approximately 11.5 min. Diaziquone produced significant growth delays in at least one experiment using each of seven different tumor lines, and it produced consistent and significant delays in five of the seven. There was no obvious difference between a single dose and a dose administered once daily for 5 days, and tumor regressions to a volume smaller than that at treatment were uncommon in any of the single-drug experiments. Using our most extensively characterized human glioma line, D-54 MG, we found striking enhancement of the therapeutic effect by using nontoxic combinations of either diaziquone and carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, NSC 409962) or diaziquone and procarbazine (NSC 77213). These combinations produced significant increases in the median growth delay, significant increases in the number of tumor regressions, and some instances in which no palpable tumors were present 100 days after treatment. In contrast, in experiments using diaziquone -based chemotherapy combinations with either cyclophosphamide, cis-platinum, or vincristine, there was only slight enhancement of the therapeutic effect. These results, using human glioma and medulloblastoma tumor lines in athymic mice, suggest a broad range of activity of diaziquone against primary nervous system tumors and enhancement of its therapeutic effect with either 1,3-bis(2-chloroethyl)-1-nitrosourea or procarbazine. If Phase II and Phase III clinical trials corroborate these findings, the value of the nude mouse system for the evaluation of new therapeutic approaches to brain neoplasms would be further confirmed.

Animals↗
PubMed1983

Interactions of ozone and antineoplastic drugs on rat lung fibroblasts and Walker rat carcinoma cells.

Cultured rat lung fibroblasts (F-cells) and Walker rat carcinoma cells (WRC-cells) labeled with 51Cr were exposed to the following antitumor drugs alone or with O3: carmustine (BCNU), doxorubicin (Dox), cisplatin (CPt), mitomycin C (Mit C) or vitamin K3 (Vit K). Release of 51Cr (cell injury) was greater for F-cells than WRC-cells with any single treatment. Pretreatment with any drug (400 microM), except for Vit K with WRC-cells, did not significantly increase O3-induced loss of 51Cr. Co-exposure of F-cells to drugs and O3 resulted in a marked potentiation of O3-induced injury with Vit K, and an inhibition with Dox.

Animals↗
PubMed1982

Hematopoietic stem cells in Friend murine leukemia virus-infected mice undergoing chemotherapy: effects of 5-FU.

Uninfected DBA/2 mice and those infected 12 days previously with the polycythemia-inducing Friend murine leukemia virus were treated with 5-FU in doses of 18.75--200 mg/kg ip, and the effects on spleen weight, reticulocytosis, and hematopoietic stem cell compartments CFU-S, CFU-C, and CFU-E was studied. The CFU-E population of virus-infected mice, which had been completely independent of erythropoietin (Ep) in vitro before treatment, showed a considerable proportion of normal Ep-requiring CFU-E at Days 2--6 after doses less than or equal to 50 mg/kg, indicating a chemotherapy-induced remission. Later, Ep-independent growth was seen again, most probably due to a reinfection by the virus at the target cell level. The regeneration of all stem cell types was quicker in uninfected mice than in those infected with virus. These data are discussed in relation to results obtained with hydroxyurea treatment, where Ep-dependent CFU-E were also seen, and with respect to the effects of busulfan, carmustine, and dactinomycin, with their different modes of actin. The importance of effective antiviral therapy for the cure of such a virus-induced malignancy is emphasized.

Animals↗
PubMedDate not supplied

EGF-effects in vitro and in vivo on a carcinoma cell line rich in EGFR.

T-CAR1 is a human carcinoma cell line established from a brain metastasis. The tumour cells overexpress EGFR and contain an amplified EGFR gene. In vitro in the presence of 5% human serum the tumour cells grow as adherent cells in monolayer. Shortly after exposure to EGF a large number of tumour cells round up and detach, whereas some remain adherent. At the same time a redistribution of actin occurs. Cytochalazin B prevented this reaction, which indicates that actin is involved in the detachment of the tumour cells. The EGF-detached tumour cells however, did not differ from the tumour cells which remained adherent after EGF-exposure with regard to parameters such as growth in soft agar, growth response to EGF, tumour necrosis factor-alpha, interferon-gamma, and carmustin (BCNU), level of EGFR gene expression and EGFR gene amplification, S-phase fraction, and amount of DNA. It was speculated whether the EGF-induced cellular detachment in vitro could be correlated to metastatic potential in vivo or not. In order to address this issue, in vivo studies with subcutaneous T-CAR1 tumours in nude mice were performed. Administration of EGF resulted in growth stimulation in contrast to growth inhibition in vitro, whereas no effect of EGF on the metastatic potential was observed. Thus, the EGF-mediated tumour cell detachment seems to be restricted to in vitro conditions only.

Actins↗