摘要:

The metabolism of 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-phosphate (F-araAMP), a soluble nucleoside analog with promising antitumor activity, has been studied in mice bearing P388 leukemia. Upon i.p. injection of an LD10dose (1485 mg/kg) in tumorbearing mice, F-araAMP disappeared from the ascitic fluid with a T½of 1.2 h. This was accompanied by the appearance of 9-β-D-arabinofuranosyl-2-fluoroadenine and lesser amounts of 9-β-D-arabinofuranosyl-2-fluorohypoxanthine in both the ascitic fluid and plasma. The principal active metabolite, 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-triphosphate, accumulated to approximately 1 mMin P388 cells, a concentration nearly 20-fold greater than that of the bone marrow or intestinal mucosa. DNA synthesis was inhibited to a similar extent in tumor and host tissues, but the duration of maximum inhibition was twice as long in P388 cells. 2-Fluoro-ATP, a second toxic metabolite, accumulated to 27μMin P388 cells and was eliminated with a T½ of 3.7 h. The contributions of both 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-triphosphate and 2-fluoro-ATP to the cytotoxicity and therapeutic action of F-araAMP should be considered in evaluations of the biochemical bases for the

ISSN:0732-9482    

DOI:10.1089/cdd.1983.1.1

年代:1983

数据来源: MAL

摘要:

A study was conducted to elucidate functional or chemical parameters that may be useful forin vivotoxicologic and pharmacokinetic analysis of PCNU. The growth-inhibitory and DNA-related parameters of this agent and its serum breakdown products in murine leukemia L1210 cells were carried out in direct comparison with BCNU. In human and dog sera, the T½ of intact PCNU (5-12 min) was similar to BCNU (5-16 min). However, much larger T½ values for PCNU (140 min) and BCNU (110 min) were determined for drug incubated in dog brain homogenates. Uptake of14C-labeled PCNU in L1210 cells was rapid, and tenfold higher than in CCRF-CEM, a human leukemia cell line naturally resistant to BCNU and PCNU. BCNU was shown to induce DNA strand damage in L1210 and to inhibit radioactive thymidine incorporation into DNA and cross-link proteins with DNA in L1210. PCNU, by comparison, only weakly inhibited thymidine incorporation and did not induce DNA strand breakage or produce DNA-protein cross-links in L1210 at reasonable concentrations. The compounds are further differentiated in fetal calf serum by the breakdown products derived from initial concentrations of intact drug that are equipotent; those of BCNU inhibit L1210 growth whereas those of PCNU do not. PCNU, which is rapidly broken down into inactive metabolites, may have a selective therapeutic advantage if infused directly to the target sit

ISSN:0732-9482    

DOI:10.1089/cdd.1983.1.11

年代:1983

数据来源: MAL

摘要:

Tumor cell membranes were susceptible to the action ofClostridium perfringensphospholipase C, and this was reflected by inhibition of cellular replication in culture. The differential susceptibility of two neoplastic cell lines to this enzyme was studied in detail. The growth of sarcoma 180 cells cultured in Fischer's medium was markedly inhibited by phospholipase C; whereas, in contrast, cultured L1210 leukemia cells were relatively resistant to the cytotoxic effects of this enzyme. The differential sensitivity of these two neoplastic cell lines to phospholipase C was corroborated by dye-exclusion tests. Thus, leukemia L1210 cells exposed to a concentration of 0.2 mg of phospholipase C per ml of Fischer's medium for 30 min at 37°able to exclude Trypan Blue; whereas, only about 21% of sarcoma 180 cells treated under identical conditions were able to exclude the dye. That the cytotoxicity of phospholipase C to sarcoma 180 was the result of hydrolysis of phospholipids of the plasma membrane was supported by measurements of the rate of hydrolysis of radioactivity from the phospholipid of neoplastic cells prelabeled with [3H]choline. Eighty-two percent of incorporated radioactive choline was released from sarcoma 180 cells treated with phospholipase C in Fischer's medium, whereas, only 20% of the label from [3H]choline was solubilized from 1.1210 leukemia cells treated with the enzyme under similar conditions. Scanning electron microscopy revealed significant damage to sarcoma 180 cells exposed to phospholipase C in Fischer's medium, which was characterized by alterations in size and shape of cells, disappearance of microvilli, and appearance of fistulas in cell membranes; relatively resistant L1210 leukemic cells did not appear to be markedly damaged by comparable enzyme treatment. Exposure of leukemia L1210 cells to phospholipase C in Puck's saline A increased the sensitivity of these cells to enzymatic action. Under these conditions, a comparable amount of phospholipid was hydrolyzed from surface membranes of sarcoma 180 and leukemia L1210 cells, and the degree of membrane damage appeared to be similar, as measured by the capacity of the tumor cell lines to exclude Trypan Blue and by scanning electron microscopy. The extensive damage to membranes by hydrolysis of phospholipids was not accompanied by a change in the degree of specific binding of |3H|concanavalin A(ConA). The use of arabinosylcytosine (araC) and 5-azacytidine, two agents with the ability to inhibit the biosynthesis of phospholipids, in combination with phospholipase C resulted in synergistic inhibition of the growth of L1210 leukemia cells, suggesting complementary inhibition at the level of membrane lipids. The results support the concept that (i) modification of membrane phospholipids, and possibly other structural and functional components of the cell surface, may be a useful approach to cancer chemotherapy, and (ii) synergistic inhibition of tumor cell growth can be obtained by a complementary mechanism directed at the level of phospholipids

ISSN:0732-9482    

DOI:10.1089/cdd.1983.1.21

年代:1983

数据来源: MAL

摘要:

Incorporation of amphotericin B (AMP-B) into phospholipid vesicles (liposomes) has been shown previously to decrease AMP-B toxicity while retaining the antifungal efficacy of the drug. In this report, the role of sterols in the formulation of liposomes as well as in their effectiveness in the treatment of murine candidiasis have been investigated. The presence of ergosterol or cholesterol at different lipid ratios did not augment the encapsulation efficiency of AMP-B as compared with vesicles containing phospholipids alone. There was no significant difference in the survival time of mice infected withCandida albicanstreated with sterol-containing vesicles compared with those treated with sterolfree vesicles. These findings suggest that the sterol-free liposomes might be of advantage for delivering AMP-B because of its simple formulation, lack of toxicity, and ease of preparation.

ISSN:0732-9482    

DOI:10.1089/cdd.1983.1.37

年代:1983

数据来源: MAL

摘要:

The toxicity and therapeutic efficacy of free adriamycin (AM) and AM entrapped in standardized liposomes (AM-MLV) were evaluated in normal mice and in mice bearing M 5076 murine tumor, which metastasizes to the liver after i.v. and s.c. transplants of tumor cell suspensions. Acute and chronic toxicity to AM could be reduced by drug encapsulation in liposomes. The data indicated that at approximately equitoxic doses of free AM (10 mg/kg) and AM-MLV (>20 mg/kg), the increase in survival times of mice transplanted i.v. with tumor cells were 25% and 100%, respectively. Furthermore, only in the AM-MLV-treated mice were long-term survivors observed. In contrast AM-MLV were equally effective as free AM in mice transplanted s.c. with tumor cell suspensions. AM-MLV, however, were more effective than free AM against liver metastases in mice bearing s.c. tumor, indicating differential antitumor activities against the same tumor type growing at different locations in the same animals.

ISSN:0732-9482    

DOI:10.1089/cdd.1983.1.43

年代:1983

数据来源: MAL

摘要:

To assess the therapeutic effectiveness of methotrexate (MTX) when administered in a liposome carrier, mice bearing intracranial L1210 leukemia were tested with liposomal MTX, free MTX, or saline. Single i.p. injections of liposomal MTX at doses of 5 mg/kg and 2.5 mg/kg prolonged survival of mice bearing intracranial L1210 leukemia. The same doses of the free drug did not prolong survival of the tumor-bearing mice. This system may have clinical application not only for MTX, but also other polar anticancer agents in the treatment for central nervous system malignancy.

ISSN:0732-9482    

DOI:10.1089/cdd.1983.1.59

年代:1983

数据来源: MAL

摘要:

Hepatic arterial infusions of streptozocin (STZ) were compared with peripheral venous infusions administered for 3 h at a dose rate of 0.5 or 1.0 g/m2. h in five patients with liver-predominant neoplastic disease. Peripheral venous plasma STZ levels were measured during and for 3 h after completion of all infusions. Steady-state was achieved at 2 h and the elimination half-life was 35-40 min, the total body clearance was 400 ml/min, and the volume of distribution of STZ was 20-22 liters in these patients. Comparison of steadystate drug levels demonstrated minimal hepatic extraction (mean 5%). Assuming a hepatic arterial blood flow of 100-200 ml/min with a total body clearance of 400 ml/min, hepatic arterial administration of STZ can be expected to result in a three- to sixfold greater exposure of tumor in the liver compared with the intravenous route. Toxicity was minimal and two patients had evidence of response.

ISSN:0732-9482    

DOI:10.1089/cdd.1983.1.63

年代:1983

数据来源: MAL

摘要:

A total of 49 patients were treated using intraarterial cis-platinum infusions at a dose of 100 mg/m2. The patients were separated into three groups. There were 13 patients with metastatic tumors, 10 with recurrent malignant gliomas, and 22 patients with high-grade gliomas who received intraarterialcis-platinum as part of an adjuvant program. In addition, four nongliomatous primary brain tumors were treated in this fashion.Cis-platinum was filtered immediately prior to intraarterial infusion using a 0.22-μm filter. Response to treatment was evaluated by follow-up CAT scans and neurologic examinations. There were three complete and eight partial responses in metastatic tumors, and eight partial responses in recurrent gliomas. The median survival was 19 weeks for patients with metastatic disease, and 16 weeks for patients with recurrent gliomas. Those high-grade glioma patients who received intraarterialcis-platinum as adjuvant chemotherapy along with CCNU and radiation therapy had a projected median survival of 91 + weeks. Toxicity from intraarterialcis-platinum following drug filtration was markedly reduced when compared with previous reports. Only five patients experiencing visual or central nervous system toxicity utilizing filtered cis-platinum and no radiographic or histopathologic evidence of central nervous system toxicity was observed. Bilateral deafness was observed following vertebral artery infusion in both patients treated in this manner and thus vertebral artery infusions should be avoided. Systemic toxicity was mild. Intracarotid infusion is a safe, well-tolerated delivery system for filteredcis-platinum with a high response rate for patients with both metastatic and primary malignant brain tumors

ISSN:0732-9482    

DOI:10.1089/cdd.1983.1.69

年代:1983

数据来源: MAL

摘要:

Acute graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation is the most significant limiting factor preventing the widespread application of transplant therapy in acute leukemia and aplastic anemia. GVHD is mediated by T cells that contaminate harvested marrow in proportions ranging from 5-50% of the mononuclear cell population. T cell depletion (TCD) of large volumes of human marrow by E-rosetting for 24 h at 4°C with modified sheep erythrocytes achieves removal of ≥97% of all T cells, as judged by cytofluorographic analysis of the T-depleted bone marrow population with a broad panel of anti-T cell monoclonal antibodies, and abrogates functional T cell activity. Although T-depleted bone marrow cell recoveries were 2 logs below total harvested buffy coat cell numbers, the TCD mononuclear population was more than 99% viable and was enriched twofold for Ia*cells as judged by cytofluorographic analysis. This method is at least the equivalent of those employing lectin column or monoclonal antibody/complement lysis techniques and is simpler to perform. Successful engraftment of adult patients can safely be obtained with as few as 4 X 108total mononuclear cells following the 24-h procedure suggesting that prolonged or repeated T-depletion procedures do not interfere with stem cell engraftment. Preliminary results suggest that this method of TCD may ameliorate GVHD in histoincompatible transplan

ISSN:0732-9482    

DOI:10.1089/cdd.1983.1.79

年代:1983

数据来源: MAL

ISSN:0732-9482    

DOI:10.1089/cdd.1983.1.87

年代:1983

数据来源: MAL