摘要:

By using increased doses or dose intensities of cytostatic agents, improvements in clinical outcome may be achieved in some cancer cases. However, high-dose chemotherapy may produce dose-limiting adverse reactions such as myelosuppression, neurotoxicity, cardiotoxicity, gastrointestinal toxicity, nausea and vomiting. The use of bone marrow transplantation, autologous infusion of circulating hematopoietic progenitors and hematopoletic growth factors have been shown to significantly reduce the severity and duration of the pancytopenia associated with cytostatic chemotherapy and chemoradiotherapy. In addition, recent developments in the control of nausea and vomiting with selective 5-HT3antagonists have improved the tolerability of chemotherapy. The antiemetic efficacy of these agents has been shown to be equivalent to combination therapy with metoclopramide plus dexamethasone in the prevention of cisplatin-induced emesis. Progress in the prevention and treatment of organ toxicity is now required, if treatment with higher doses and dose intensities of cytostatic drug treatments are to be used for the future treatment of human malignancies.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The aim of this review is to summarize currently available information on the rapid screening and Initial characterization of the different mechanisms of resistance to hydrophilic [e.g. methotrexate (MTX)] and lipophilic antlfolates [e.g. trimetrexate (TMTX)] in cultured mammalian cells using fluorescein-methotrexate (F-MTX) and flow cytometry. Toward this end an integrative F-MTX labeling and flow cytometry-based protocol is proposed here to facilitate the rapid identification of modes of antifolate resistance in a heterogenous drug-resistant cell population or in clonal derivatives. Following antifolate selection, drug-resistant cells are first labeled with F-MTX In order to saturate Intracellular dihydrofolate reductase (DHFR). F-MTX-labeled cells are then subjected to flow cytometric analysis and mean fluorescence/cell is determined. Thus, increased F-MTX staining is an indication of overproduction of the target enzyme for antifolates, DHFR, as a result of DHFR gene amplification. In contrast, significantly reduced cellular F-MTX labeling could be an indication of the existence of a structurally altered DHFR displaying a decreased affinity for antifolates. Alternatively, antifolate-resistant cells frequently display wild-type F-MTX labeling; these cells are subjected to competition with hydrophilic and lipophilic antifolates in order to examine whether the process of antifolate accumulation is deficient. Cells that lose F-MTX labeling upon competition with lipophilic antifolates yet still retain it with hydrophilic antifolates, are likely to possess transport alteration(s) that Impair or abolish the accumulation of hydrophilic but not of lipophilic antifolates. In contrast, cells that lose their F-MTX labeling after competition with hydrophilic antifolates but retain it with lipophilic antifolates, possess a deficient accumulation of lipophilic antifolates. The importance of the antifolate concentration yielding 50% displacement of cellular F-MTX labeling in the quantitative assessment of the degree of DHFR overexpression and/or antifolate transport alteration is discussed. Thus, flow cytometric analysis of F-MTX-labeled cells following competition with hydrophilic and lipophilic antifolates provides a useful tool for the rapid screening and assessment of the major modes of antifolate resistance that may appear as exclusive mechanisms or co-emerge in mammalian cells following antifolate selection.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

We developed an assay which permits measurement of aspartate carbamoyltransferase (ACTase) activity. Cytosol from human peripheral blood mononuclear cells was used as the enzyme source. Using [14C]carbamoyl phosphate as the radiolabeled substrate, the formation of [14C]carbamoyl aspartate was quantitated by high performance liquid chromatography (HPLC) using an anion-exchange column with UV detection at 200–280 nm and an on-line liquid scintillation detector. A gradient method from an initially low concentration of ammonium phosphate, 1 mM (pH 3.0), to a higher concentration, 38 mM (pH 4.5), was used. The apparentKmvalues of carbamoyl phosphate and aspartate were 58μM and 1.9 mM, respectively. ACTase inhibition byN-Mphosphonacetyl)-1-aspartate (PALA) was consistent with a competitive model with respect to carbamoyl phosphate. The assay conditions were optimized to permit measurement of ACTase activity prior to and following therapy with PALA; ACTase was inhibited in a dose-dependent manner. This HPLC method permits direct quantitation of both the product of the reaction and the initial integrity of the substrate, [14C]carbamoyl phosphate, which is unstable in aqueous solutions.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Increased activity against colorectal cancer by 5-fluorouracil (5-Fu) modulation with leucovorin (LV) and/or interferon (IFN) has been reported. In this study 22 patients with measurable advanced pancreatic cancer received 5-Fu 375 mg/m2and LV 20 mg/m2by i.v. bolus daily × 5 every 28 days plus IFN-α 3 million units/m2s.c. There were three out of 21 (14%) responses lasting from 4 to 8 months. Sixteen patients (73%) had one or more episodes of grade 3 or greater toxicity (stomatitis, diarrhea or fatigue). While this combination has some activity against pancreatic cancer, its toxicity limits its potential as a palliative treatment.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Studies in which high-dose methotrexate (HDMTX) is used for the treatment of osteosarcoma have utilized commercial formulations of d,l-leucovorin (leucovorin calcium) for rescue from potential methotrexate (MTX) toxicity. These formulations are racemic mixtures containing equal amounts of d and l isomers of leucovorin. All of the available data indicate that the l isomer is the pharmacologically active diastereomer. A clinical study was conducted to determine if l-leucovorin was as safe and efficacious as d,l-leucovorin in the rescue of patients with osteosarcoma who were treated with HDMTX (12.5 g/m2over 6 h). Because d,l-leucovorin consists of equal proportions of d and l isomers, l-leucovorin was administered at half the usual dose of d,l-leucovorin. In patients with delayed methotrexate excretion, l-leucovorin doses were escalated from 7.5 to 50 mg every 3 h until the MTX level was 0.3 μmol/l or less. Due to the low Incidence of osteosarcoma, a control group of patients previously treated with d,l-leucovorin was utilized for comparison. Efficacy of l-leucovorin was determined by Its ability to prevent HOMTX-associated toxicity. Demographic and clinical toxicity data from three patients who received 22 courses of MTX rescued with l-leucovorin were compared with data from six patients who had received 42 MTX courses rescued with d,l-leucovorin. Some liver function abnormalities and leukocyte elevations were found in both groups and were attributed to MTX administration. No clinical toxicity attributable to l-leucovorin was observed. l-Leucovorin in half the d,l-leucovorin dose was (equally) effective as a rescue treatment.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Several studies showed that thymic factors and prostaglandin synthesis inhibitors enhancein vitrolymphoproliferative response (LPR) to mitogens in cancer patients. In this study we investigated whether indomethacin and thymic extract (Thymex L), applied in combination, may in a synergistic pattern influence phytohemagglutinin-induced LPR in lung cancer patients. The results demonstrate that the use of the investigated agents enhances LPR to a similar level in hyporeactive patients before, as well as after, therapy. However, this drug combination exerts an additive effect on LPR, but only in patients who underwent cytoreductive radiation therapy, indicating the potential usefulness of this drug combination as an adjuvant treatment of these patients.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Twenty-seven tumor specimens from patients with Merkel cell carcinoma (MCC) were tested for chemosensitivity against a battery of nine cytotoxic drugs in a short-term antimetabolic assay measuring inhibition of thymidine incorporation. Dose-response curves were constructed by plotting drug concentration in μg/ml versus % control [3H]thymidine incorporation. Specimens were considered ‘sensitive’ to a drug if, at the approximate peak plasma concentration (PPC), the inhibition of [3H]thymidine was greater than 50% when compared with untreated control primary cultures. The assay revealed a ‘sensitive’ tumor in 19 of 20 specimens and 16 of 17 patients had a tumor that was ‘sensitive’ to at least one drug tested in the assay system. The highest sensitivity in order of frequency was found with doxorubicin, epirubicin, cyclophosphamide, etoposide and cisplatin. At least 40% of the tumors were ‘sensitive’ to these five drugs. Cyclophosphamide was chosen as the most active drug (at PPC) in 10 of 19 assays (53%), etoposide in seven of 17 (41%), doxorubicin in four of 19 (21%), chlorambucil in one of 12 (8%) and cisplatin in one of 18 (5%) of assays. Though our results are preliminary, we have identified for the first time a range of cytotoxic drugs which appear effective against MCCin vitro. Our main task now is to determine whether ourin vitropredictive assay will correlate with clinical benefit to the patient.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Thein vivocombination effect of navelbine (NVB, KW-2307) plus cisplatin was compared with that of vindesine (VDS) plus cisplatin In terms of antitumor activity and side effects. The antitumor activity of NVB or cisplatin against i.p. inoculated P388 leukemia was augmented by their combination on various schedules when the interval of administrations was within 24 h. Against i.v. inoculated P388 leukemia, the most significant combination effect was observed when cisplatin was administered 4 h after NVB injection (ILS(%) > 451) and three long-term survivors were observed. On this schedule, the combination of LD10of each drug was achieved, indicating the lack of addition of toxicity. This was further proved by examination of body weight change, white blood cell count and platelet count. Interestingly, significant elevation of blood urea nitrogen concentration by cisplatin was prevented by the combination with NVB. The combination of maximum tolerated dose of NVB and cisplatin was also tolerable in nude mice, and their combination effect was observed against human lung large cell carcinoma Lu-65 and adenocarcinoma PC-12. The number of toxic death mice was more in VDS plus cisplatin-treated groups than in NVB plus cisplatin-treated groups, indicating that the combination chemotherapy of NVB plus cisplatin is a better regimen than that of VDS plus cisplatin in experimental tumor systems.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The progression of advanced malignancies is often associated with anorexia and cachexia, especially when patients receive concomitant systemic antitumor treatment. Megestrol acetate has been reported to increase appetite and body weight, and a linear dose-response relation for doses from 160 up to 1600 mg/day has been proposed. In our study, we were able to show that megestrol acetate at doses as low as 60 mg/day was sufficient to abrogate anorexia and weight loss. In contrast to previous studies, this effect was achieved while patients continued systemic antineoplastic therapy.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID