摘要:

AbstractIn an attempt to define the activity and toxicity of low-dose aminoglutethimide plus steroid replacement in advanced breast cancer, we treated 40 patients with aminoglutethimide 500 mg/day + hydrocortisone 50 mg/day. Previous treatment consisted of additive hormones in 29 patients, oophorectomy in 8, and chemotherapy in 32. Among the 37 patients evaluablefor response and toxicity, 5 objective responses (16.2%) and 20 stable diseases (54%) were noted. Toxicity, absent in 23 patients (62.I %) and mild in 14, consisted mainly of Grade I (WHO) nausea, drowsiness, cutaneous rash, and dizziness. Responders and patients with stable disease experienced a similar survival (median not reached at 22 months). Aminoglutethimide at low doses appears to be beneficial in patients refractory to conventional therapies even if the objective response rate is low.

ISSN:0735-7907    

DOI:10.3109/07357908909038277

出版商:Taylor&Francis    

年代:1989

数据来源: Taylor

摘要:

AbstractWe have investigated the genotoxicity of BIDA in cultured human lymphocytes. Lymphocytes were cultured and stimulated with phytohemagglutinin (PHA) for 72 h. Doses of 0.1, 0.25, 0.5, 0.75, and 1 fig/ml of BIDA were added to the culture at 1 h (G2 phase), and 6 h (S/G2 phase) before harvesting. Cells were harvested at the end of the 72-h culture period with 1-h colcemid treatment to accumulate mitosis, and further prepared by standard cytogenetic technique. BIDA induced chromatic type breakages and chromatid exchanges at both 1 h and 6 h. The mean number of breakages per cell was 0, 0.1, 1.0, and 1.7 after treatment with 0.1, 0.25, and 0.75 kg/ml, respectively. At 1 kg/ml, BIDA severely inhibited cell progression and very few mitoses were observed. At 6 h the mean number of breakages per cell was 0.3 at 0.25 fig/ml and 1.2 at 0.5 kg/ml. Very few cells entered mitosis at 0.75 and 1 kg/ml. To study the effect of BIDA on cells in G0and G1, BIDA (0.75 kg/ml) was added for 1 h to the cultures at the beginning of culture (G0), or 24 h after (G1) culture initiation. Afterward, cells were washed and reincubated in the conditioned medium for 71 or 47 h. No chromosomal aberrations were seen in these experiments. The number of chromatid breaks was minimal (0.1 to 0.4/cell). Our study suggests that BID A induces chromatid type aberrations during G2and S phases. The absence of chromosome type aberrations in cells treated during G0and G1suggests that either BID A has no effect on these cells or that damaged cells fail to progress through S and G2to reach mitosis.

ISSN:0735-7907    

DOI:10.3109/07357908909038278

出版商:Taylor&Francis    

年代:1989

数据来源: Taylor

摘要:

AbstractWe have utilized [3H]diacetyl-didemnin B([3H]DB) in a series of in vitro experiments to determine the time course of equilibration of[3H]DB between plasma and blood cells, the distribution of [3pH]DB among blood cells, and the distribution of [3H]DB in plasma. Within 45-60 min at 37d`C, approximately 55% of[3H]DB added to whole blood remained in the plasma. Of the drug associated with blood cells, 77% was found with the red blood cells, 18% with the lymphocytes, and 5% with the granulocytes. However, on the basis of amount of drug uptake per cell, lymphocytes incorporated nearly 400 times more and granulocytes nearly 30 times more [3H]DB than red blood cells. No specific association of [3pH]DB with a particular lymphocyte subset was detected. Additionally, it appears that [3H]DB in plasma was associated to a large extent with albumin.

ISSN:0735-7907    

DOI:10.3109/07357908909038279

出版商:Taylor&Francis    

年代:1989

数据来源: Taylor

摘要:

AbstractThe cellular metabolism of 9-β-D-arabinofiiranosyl-2-fluoroadenine 5′monophosphate (F-araAMP), a soluble nucleoside analog with proven antileukemic activity in animal and human tumors, has been studied in mice bearing P388 leukemia. Earlier studies showed markedly less in vivo accumulation of F-ara ATP the principal active metabolite, in gastrointestinal mucosa (GI) and bone marrow (BM) compared with P388 after F-araA or F-araAMP administration. To elucidate the mechanism of toxicity this work has examined the pharmacodynamics of F-araAMP anabolites, F-araATP and F-ATP, in P388 cells, BM and GI mucosa tissues after nontoxic (LD1) and toxic (LD50) doses of F-araAMP. F-araATP was the major triphosphate metabolite in acid-soluble extracts from P388 cells, BM, and GI mucosa tissues. F-araATP accumulated to approximately 1 mM in P388 cells after either LD1or LD50treatment of F-araAMP and was eliminated with a t1/2eiof approximately 5 h. The ratio of the area under the concentration-time curve (AUC 0 -∞) of F-araATP was 1.01 after the LD50over LD1doses of F-araAMP. BM and GI mucosa tissues accumulated 40-fold less F-araATP than the concentration in P388 cells. 2-Fluoro-ATP, a second toxic anabolite, accumulated in P388 cells to 156±39 pM and 447±79 pM after the two doses of the drug, respectively. The ratio of area under the curve (AUC) of F-ATP in P388 cells after the two doses of F-araAMP was 38.77, which approaches the ratio of % lethality (LD50/LD; = 50). F-ATP was also quantitated in BM and GI mucosa reaching one-fifth to one-half the concentration ofF-araATP after the LD50 dose of F-araAMP. The AUC values of F-ATP (0 - 24 h) were 9.5-to 12.5-fold higher after the LD50than after the LD1dose of F-araAMP. These results suggest that there is a selective therapeutic action of F-araAMP against P388 and that the increased cellular concentration of F-ATP in both the tumor cells and the host tissues (BM and GI mucosa) could explain the mode of toxicity of F-araAMP.

ISSN:0735-7907    

DOI:10.3109/07357908909038280

出版商:Taylor&Francis    

年代:1989

数据来源: Taylor

摘要:

AbstractRadiation is an effective modality for palliation of osseous metastases. Inpatients with a limited number of lesions, local external beam irradiation is the most expedient method of delivering radiation therapy. Complete or partial relief of pain will occur in 80-90% of patients. When metastases are widespread or when new sites continue to appear, localized external irradiation becomes logistically difficult. In such cases, hemibody irradiation has been effective with an overall response rate of 85%. However, nausea, vomiting, diarrhea, and bone marrow and pulmonary toxicity may complicate therapy. In these cases, an effective alternative is systemic phosphorus-32 (32P) or strontium-89 (89Sr). Relief of pain in the range of 60-90% has been reported. Toxicity of32Pis largely that of bone marrow suppression, while89Sr appears to be relatively marrow-sparing. In this review, we consider systemic32P or89Sr as viable options to external beam or hemibody irradiation in the presence of numerous bone metastases.

ISSN:0735-7907    

DOI:10.3109/07357908909038281

出版商:Taylor&Francis    

年代:1989

数据来源: Taylor

摘要:

AbstractThe physiologic role of cyclic adenosine monophosphate (cAMP) in the growth control of a spectrum of human cancer lines, including leukemic lines, and v-rasHoncogene-transformed NIH/3T3 cells is demonstrated by the use of site-selective cAMP analogs. These cAMP analogs, which can select either of the two known cAMP binding sites of the cAMP receptor protein, induce potent growth inhibition, phenotypic change, and differentiation (leukemic cells) of cancer cells at micromolar concentrations with no sign of cytotoxicity. The growth inhibition parallels selective modulation of cAMP-dependent protein kinase isozymes, type I versus type II, and suppression of cellular proto-oncogene expression. Site-selective cAMP analogs thus provide new biological tools for investigating cell proliferation and differentiation and also for the improved management of human cancers.

ISSN:0735-7907    

DOI:10.3109/07357908909038282

出版商:Taylor&Francis    

年代:1989

数据来源: Taylor

ISSN:0735-7907    

DOI:10.3109/07357908909038283

出版商:Taylor&Francis    

年代:1989

数据来源: Taylor

ISSN:0735-7907    

DOI:10.3109/07357908909038284

出版商:Taylor&Francis    

年代:1989

数据来源: Taylor

ISSN:0735-7907    

DOI:10.3109/07357908909038285

出版商:Taylor&Francis    

年代:1989

数据来源: Taylor

摘要:

AbstractThe concept of chemoprevention is generating increasing attention among oncologists. This article discusses the issue of dose of chemopreventive agents in relation to the stages of tumor development. Vitamin A-deficient animals have an increased susceptibility to cancer development, and epidemiologic studies have shown an inverse relationship between intake of food rich in vitamin A and/or beta-carotene and cancer risk. These data suggest that physiologic levels of these natural substances exert a protective effect against cancer development. In the presence of precursor lesions, however, this protective effect has been overwhelmed and pharmacologic doses of chemopreventive agents are required to induce regression or to arrest the progression of these lesions. Phase I pharmacologic and toxicologic studies, and Phase II dose-intensity investigation of chemopreventive agents in patients having precancerous lesions need to be carried out. Such studies would enable to select the least toxic effective chemopreventive dose for intervention trials in high-risk populations, which could then be undertaken based on evidence of activity.

ISSN:0735-7907    

DOI:10.3109/07357908909038286

出版商:Taylor&Francis    

年代:1989

数据来源: Taylor