Update on bonding brackets: an in vitro survey.
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Data Collection↗
Biomedical subjects
R A Newman
Publications and source records attributed to R A Newman.
Phenotypic markers and BCL-1 gene rearrangements in B-cell chronic lymphocytic leukemia: a Cancer and Leukemia Group B study.
The markers, CD11b, CD11c, CD14, CD21, CD23, CD25, CD38, and FMC7 were correlated with morphologic and other laboratory and clinical characteristics of 127 patients with untreated CD5+ chronic lymphocytic leukemia (CLL). Only CD38 and CD21 were significantly associated with atypical CLL morphology. The integrin associated markers CD11b and CD11c were associated with lower leukocyte count (white blood cell count [WBC]) and lower Rai stage. By contrast, the activation antigen CD23 was associated with a higher WBC, higher Rai stage, younger age group, and the presence of lymphadenopathy. Therefore, we conclude that CD23 positivity may reflect a more aggressive form of CLL, and CD11b and CD11c positivity a less aggressive form. The BCL-1 gene rearrangement was present in 5 of 84 (6%) CLL cases examined and was associated with atypical morphology and surface expression of CD11b. Patients with a BCL-1 gene rearrangement may represent a CLL subset or possibly a different B-cell disease.
Adult↗
Increased doxorubicin levels in hepatic tumors with reduced systemic drug exposure achieved with complete hepatic venous isolation and extracorporeal chemofiltration.
We evaluated a novel system of complete hepatic venous isolation and chemofiltration (CHVI-CF) to reduce systemic drug exposure following regional hepatic infusion of doxorubicin. Rabbits bearing hepatic VX-2 tumors were given doxorubicin via either hepatic arterial infusion (HAI) or portal venous infusion (PVI). A dual-balloon vena cava catheter and extracorporeal chemofilter were used to capture and filter hepatic venous blood in experimental animals. Control animals received chemotherapy without hepatic venous isolation and chemofiltration. Following a 5-min HAI of doxorubicin (3 or 5 mg/kg), control and experimental animals had similar doxorubicin levels in their livers and VX-2 tumors, but experimental animals showed a significant reduction in doxorubicin levels in systemic plasma, heart, and kidney tissue as compared with control animals (P < 0.01). HAI produced a 4-fold increase in doxorubicin levels in VX-2 tumors as compared with the drug levels obtained using PVI (P < 0.01). A single HAI of 3 mg/kg doxorubicin in animals treated with CHVI-CF produced marked tumor necrosis at 7 and 14 days after treatment. By increasing the total body clearance of doxorubicin, this system will allow HAI of higher doses of drug in attempts to improve the antitumor response.
Animals↗
Treatment of a high angle case with idiopathic bilateral mandibular hypoplasia, condylar and fossa erosion, and chronic rheumatoid arthritis.
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Adult↗
2'-deoxy-5-azacytidine increases binding of cisplatin to DNA by a mechanism independent of DNA hypomethylation.
The chemotherapeutic agents 2'-deoxy-5-azacytidine (DAC) and cisplatin (cDDP) have been shown in vitro to be synergystic in their cytotoxicity toward human tumour cells. We have investigated possible molecular mechanisms underlying this synergy using the plasmid pSVE3 in vitro and after transfection into CMT3 cells. Increased binding of cDDP to DAC-substituted DNA generated in vivo was confirmed by flameless atomic absorption spectrophotometry (FAAS). The plasmid used in these experiments was unmethylated suggesting that DAC was effective in enhancing cDDP binding to DNA without acting as a hypomethylating agent, but by directly changing the topology of DNA. The role of DNA methylation in cDDP binding was studied using methylated and unmethylated plasmid incubated in vitro with cDDP. Restriction analyses and FAAS measurement of bound platinum indicated that methylated DNA bound more cDDP than unmethylated DNA. In addition, in vivo studies confirmed the in vitro observations since replication of methylated plasmid was inhibited to a greater extent than unmethylated plasmid.
Azacitidine↗
Phase I evaluation of all-trans-retinoic acid in adults with solid tumors.
PURPOSE: Prompted by recent demonstrations that all-trans-retinoic acid (all-trans-RA) had efficacy in acute promyelocytic leukemia, a phase I trial of all-trans-RA was conducted to establish the maximum-tolerated dose (MTD) before phase II testing. PATIENTS AND METHODS: Forty patients with a histologic or cytologic diagnosis of malignancy other than leukemia were treated with single daily oral doses of all-trans-RA ranging from 45 mg/m2 to 200 mg/m2. Doses of all-trans-RA were escalated in the next cohort of patients until the MTD was determined if the preceding dose level was not associated with significant toxicity. RESULTS: Lung cancer was the most common type of tumor included in the study (26 cases) followed by head and neck squamous cell carcinomas (three cases), and squamous cell carcinoma of the skin (two cases); other miscellaneous solid tumors were also represented. Toxicities included cheilitis, skin reactions, headache, and nausea and vomiting, as well as transient elevations of liver enzymes and triglyceride levels. Skin toxicities, consisting of erythema with desquamation and paronychia, were considered to be the dose-limiting toxicity, and were observed in two of six patients who received 175 mg/m2/d, and in two of five patients who received 200 mg/m2/d. Of the 30 patients with assessable lesions, response was evaluated in 26 patients and no major objective tumor response was observed. Two patients were able to receive the drug for longer than 1 year without significant toxicities. There was considerable variation in individual patients' peak plasma all-trans-RA levels, and a decrease in the area under the curve of all-trans-RA plasma concentration was observed in all four patients evaluated. CONCLUSION: For phase II study of adult patients, we recommend 150 mg/m2 of all-trans-RA administered orally once a day. However, for better optimization of drug administration schedules, further studies are needed.
Adult↗
Depletion of patients' plasma tryptophan using tryptophan side-chain oxidase columns.
The use of the enzyme tryptophan side-chain oxidase, isolated from Pseudomonas XA, was explored in 3 patients with refractory acute lymphocytic leukemia. Patients were given either a low-tryptophan diet or tryptophan-free hyperalimentation, prior to and during therapy. Their plasma, separated by pheresis, was continuously passed through a tryptophan depletion column containing the immobilized tryptophan side-chain oxidase. Up to 4 plasma volumes were passed through the column daily, 5 days per week for 2-3 weeks, and plasma tryptophan levels, both free and total, were measured by high-performance liquid chromatography. Pre- and postcolumn plasma samples were collected throughout the pheresis procedure. All postcolumn plasma samples had unmeasurable tryptophan levels throughout the treatment period, whereas precolumn samples were always measurable. Generally, tryptophan levels of plasma isolated from peripheral blood decreased after therapy, but rebounded by the next day. The enzyme depletion column reduces circulating plasma tryptophan levels, and its use is well tolerated by patients. However, further development of this method will require study of the effects of diet and of the duration, interval, and frequency of use of this column on therapeutic efficacy. Problems include difficulties with extended diet compliance and apparently intensive mobilization of tryptophan from body stores, which may preclude the clinical application of this enzyme depletion column.
Chromatography, High Pressure Liquid↗
Reduction of systemic drug exposure after hepatic arterial infusion of doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration.
BACKGROUND: Hepatic arterial infusion of doxorubicin has produced tumor response in hepatic malignancies; however, the limited success of these treatments is related in part to dose-limiting systemic toxicities. The purpose of this study was to determine whether a novel venous isolation-chemofiltration system could limit systemic exposure to doxorubicin after hepatic arterial infusion. METHODS: Doxorubicin (1 or 3 mg/kg) was infused in the hepatic arteries of domestic pigs after complete hepatic venous isolation was achieved with a dual-balloon vena cava catheter. The hepatic vein effluent was pumped through an extracorporeal carbon chemofiltration circuit. Doxorubicin levels were measured in prefilter (hepatic vein), postfilter, and systemic serum at intervals up to 1 hour after drug infusion. RESULTS: Complete hepatic venous isolation with extracorporeal chemofiltration significantly reduced (> 90%) the postfilter and systemic levels of doxorubicin compared with prefilter levels (p < 0.01). At the time animals were killed 7 days after infusion of doxorubicin (3 mg/kg), tissue levels of doxorubicin in the liver showed a 16-fold increase compared with levels in the heart (p < 0.01). CONCLUSIONS: For chemotherapeutic drugs like doxorubicin with a low first-pass extraction by the liver, the novel system described herein achieved significant reduction in systemic drug exposure. This system will allow dose intensification of doxorubicin administered by hepatic arterial infusion to treat hepatic malignancies.
Alanine Transaminase↗
Phase I trial of Taxotere: five-day schedule.
BACKGROUND: Taxotere, a semisynthetic compound structurally related to taxol, has a broad spectrum of activity in murine transplantable tumors; in the B16 melanoma model, it caused a total log cell kill 2.5 times greater than that caused by taxol at equitoxic doses. PURPOSE: We conducted a phase I study of Taxotere (a) to determine its qualitative and quantitative toxic effects and a starting dose for phase II trials, (b) to investigate its clinical pharmacology, and (c) to document its antitumor activity. METHODS: Taxotere was given as a 1-hour infusion at a starting dose of 1 mg/m2 per day for 5 consecutive days. The 5-day course of therapy was repeated every 21 days. Thirty-nine cancer patients with advanced disease were entered in the study; at least three patients were entered at each dose level. Initial dose escalations were planned at 100% increments until biologic activity was observed; subsequent escalations were planned at 50% increments until grade 2 toxicity (the National Cancer Institute's Common Toxicity Criteria) occurred and then at 25% increments until the maximum tolerated dose was established. RESULTS: Thirty-nine patients were entered in the study. Successive dose levels used were 1, 4, 8, 16, 12, and 14 mg/m2 per day. The dose-limiting toxic effects were granulocytopenia and concurrent mucositis. Grade 4 granulocytopenia associated with grade 3 mucositis developed in six of 12 patients treated at a dose of 16 mg/m2 per day, two of 10 treated at 12 mg/m2 per day, and two of eight treated at 14 mg/m2 per day. Because these toxic effects occurred concurrently, all patients so affected developed neutropenic fevers and required hospitalization. Neither cardiac nor neurologic toxic effects were noted. Anti-tumor activity was observed in six patients with ovarian cancer and in one with breast carcinoma. Although pharmacokinetic parameters were consistent between day 1 and day 5 for individual patients, considerable variation existed among those treated at the same dose level. A relationship was observed between the area under the curve for plasma concentration of drug x time (AUC) on day 1 and the percentage decrease in absolute granulocyte counts. CONCLUSION: Granulocytopenia associated with oral mucositis is the dose-limiting toxicity of this schedule. We recommended a starting dose of 14 mg/m2 per day for phase II studies of this 5-day schedule. Dose modifications on days 2-5 based on the day-1 AUC may allow individualized dosing.
Adult↗
Resistance of human cervical carcinoma cells to tumor necrosis factor correlates with their increased sensitivity to cisplatin: evidence of a role for DNA repair and epidermal growth factor receptor.
Alterations in cellular biochemistry which are associated with the development of resistance to cytotoxic peptides, such as tumor necrosis factor (TNF), may also be responsible for changes in the response of cells to cytotoxic agents. Culturing ME-180 cervical carcinoma cells in the presence of escalating concentrations of TNF resulted in the development of an ME-180 cell variant (ME-180R) resistant to TNF but expressing a 3-5-fold increased sensitivity to cisplatin (CDDP) when measured following continuous exposure (low doses) or short-term incubation with CDDP (high doses) and clonogenic analysis. Cellular platinum uptake, efflux, and nuclear platinum content as well as the extent of DNA platination were examined and found to be identical in both ME-180 parental and ME-180R cell lines. Although ME-180R cells showed a relatively higher glutathione content than ME-180 parental cells, the effect of buthionine sulfoximine on the cellular sensitivity to CDDP and glutathione S-transferase activities of both cell lines were almost identical, suggesting that glutathione content or its metabolism did not appear to play a major role in differential CDDP cytotoxicity. Unscheduled DNA synthesis following exposure to CDDP was more inducible in ME-180 parental cells than in CDDP-sensitive ME-180R cells. Alkaline elution studies of cross-linked DNA in CDDP-treated ME-180 cells suggested that accumulation of DNA adducts reached maximal levels 10-15 h after CDDP treatment and was similar in both TNF-resistant and parental cells. Within 24 h after CDDP exposure, the extent of DNA cross-linking was markedly reduced in parental cells but remained elevated in the CDDP-sensitive ME-180R cell line. To examine the proposed regulatory role of phosphorylation in CDDP and TNF-mediated cytotoxicity, epidermal growth factor (EGF) receptor tyrosine kinase activity was measured in both TNF-resistant and parental ME-180 cells. Analysis of cell lysates demonstrated a 3-4-fold higher EGF receptor tyrosine kinase activity in ME-180R cells when compared to the parental population which correlated with increased expression of EGF receptor protein by immunoblot analysis. Based upon colony-forming assays, EGF treatment of ME-180 parental cells resulted in an increased sensitivity to CDDP (similar to ME-180R cells) and 3-fold stimulation of EGF receptor tyrosine kinase activity. Taken together, these results suggest that TNF resistance in ME-180 cervical carcinoma cells correlates with both increased EGF receptor expression and enhanced CDDP cytotoxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinoma↗
Flavone acetic acid increases the antitumor effect of hyperthermia in mice.
The combined effects of flavone acetic acid (FAA), a synthetic flavonoid, and hyperthermia on B16 melanoma cells were investigated. In vitro, FAA alone at concentrations below 100 micrograms/ml was not cytotoxic with a 60-min exposure at 37 degrees C. Hyperthermia at 43 degrees C for 60 min enhanced the cytotoxicity of FAA only at concentrations over 100 micrograms/ml. Inhibition of the growth of B16 melanoma solid tumor by FAA and/or hyperthermia was examined in vivo. FAA (100-200 mg/kg) inhibited tumor growth in a dose-dependent manner. The combined treatment of FAA (200 mg/kg) and hyperthermia (43 degrees C, 15 min) significantly inhibited tumor growth compared to a treatment of FAA or hyperthermia alone. The maximum antitumor effect of FAA combined with hperthermia was obtained when FAA was administered 2 or 4 h before heat. The significantly increased cytotoxicity of FAA combined with hyperthermia seems to relate to specific decreases in tumor blood flow, a reduction in tumor pH, and an increased tumor temperature, without altering pH in the normal tissues. This combined treatment of FAA and hyperthermia warrants further study for treating subjects with solid tumors.
Animals↗
Phase I trial and clinical pharmacology of elsamitrucin.
Elsamitrucin (BMY-28090) is an antitumor antibiotic first described in 1985 that has significant oncolytic activity against a number of murine tumors including P388, L1210, B16 and M5076, as well as against MX1 and HCT116 xenografts. Preclinical toxicology studies of elsamitrucin revealed edema of multiple organs associated with hypoproteinemia and, at lethal doses, severe multiorgan toxicity. We conducted a phase I clinical trial (31 patients) of elsamitrucin administered as a 10-min i.v. infusion every 3 weeks. The starting dose (0.6 mg/m2) was 1/3 of the dog low toxic dose. The maximum tolerated dose was 30 mg/m2. Dose-limiting toxicity was reversible hepatic dysfunction manifested by elevated transaminase levels not associated with bilirubin, alkaline phosphatase, or lactate dehydrogenase elevations. Other toxicities included nausea, vomiting, malaise, and phlebitis. Because the hepatic toxicity was brief and reversible, a subsequent study (18 patients) was conducted with elsamitrucin administered every 2 weeks. Reversible grade 3 hepatotoxicity was again observed at 30 mg/m2. Plasma and urine samples from patients receiving doses of 0.6-36 mg/m2 were analyzed for drug content. The maximum plasma concentration and area under the plasma concentration versus time curve values increased linearly with doses up to 25 mg/m2 but not at higher doses. The terminal half-lives, total body clearances, and volume of distribution were 36-60 h, 10-19 liters/h/m2, and 400-1100 liters/m2, respectively. Less than 5% was excreted in the urine in 24 h as parent compound. Bile was collected from one patient with an indwelling biliary catheter. Approximately 22% of the dose was excreted in 48 h, suggesting that biliary excretion of elsamitrucin may be an important route of drug elimination. Based on reversible hepatic toxicity, the phase II recommended dose of elsamitrucin is 25 mg/m2 every 2 weeks.
Adult↗
Synthesis, characterization, and antitumor activity of new chloroethylamine platinum complexes.
A series of cis-bis-(2-chloroethylamine)platinum(II) and platinum(IV) complexes were synthesized and characterized by elemental analysis, IR, and 1H and 195Pt NMR spectroscopic techniques. Complexes were tested in vitro against murine L1210 leukemia and human ovarian A2780 cell lines and in vivo against the L1210 leukemia model. Some of these complexes showed excellent antitumor activity in both systems. However, all were inactive against cisplatin-resistant A2780/CP cells.
Animals↗
An enzyme immunoassay for determining plasma concentrations of didemnin B.
Didemnin A was conjugated at the amino terminus of the N-methylleucine residue, via the linkers N-succinimidyl-3-(2-pyridyldithio)-propionate and trans-1,4-maleimidomethyl-cyclohexane carboxylic acid, to keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA). The didemnin-KLH conjugates were used to hyperimmunize rabbits. The resulting high titer antisera were employed with didemnin-BSA conjugate-coated microtiter plate wells to develop an indirect competitive inhibition enzyme immunoassay (CIEIA) that was fully cross reactive with didemnin B. A CIEIA is described that is capable of detecting the drug in plasma from didemnin B-treated patients at concentrations down to 1-3 ng/ml. This simple, sensitive CIEIA has been employed to demonstrate plasma drug clearance profiles with samples from didemnin B-treated patients.
Antineoplastic Agents↗
A high-performance liquid chromatographic assay for CI-973, a new anticancer platinum diamine complex, in human plasma and urine ultrafiltrates.
CI-973 is a new platinum compound with antitumor properties that is currently undergoing phase II clinical trials. A high-performance liquid chromatographic (HPLC) assay was developed and validated for ultrafiltrates of human plasma and urine to support phase I clinical trials. Plasma ultrafiltrate (0.5 ml) was extracted using C18 solid-phase cartridges. Urine was diluted 10-fold and extracted first with SAX solid-phase cartridges and then with C18 cartridges. For both matrices, the eluate from the C18 cartridges was injected directly. A Whatman PAC 10 column (4.6 x 250 mm, 10-microns particle size) and ultraviolet detection at 205 nm were used for both analyses. The mobile-phase buffer was 0.05 M sodium perchlorate (pH 2.3). The mobile-phase acetonitrile:buffer ratio, column temperature, and flow rate were 89:11 (v/v), 40 degrees C, and 2.0 ml/min, respectively, for the plasma ultrafiltrate assay and 85:15 (v/v), 50 degrees C, and 1.0 ml/min, respectively, for the urine ultrafiltrate assay. Standard curves were linear from 0.25 to 500 micrograms/ml and from 1.0 to 250 micrograms/ml for the plasma and urine assays, respectively. The accuracy of the assay lay within 4.5% of the nominal values, and the precision was 6.2%; the recovery of CI-973 varied from 79.2% to 105%. CI-973 remains stable in plasma for at least 6 h, at room temperature, in ultrafiltrates of both matrices for at least 15 days at -72 degrees C, and in water for at least 6 months at -72 degrees C.
Antineoplastic Agents↗
Phase II clinical and pharmacological study of didemnin B in patients with metastatic breast cancer.
Sixteen evaluable patients with metastatic breast cancer were entered into a phase II trial of didemnin B. They received the drug at an initial dose of 5.6 mg/m2 every 21 to 28 days. Major toxicities noted were myalgia and nausea and vomiting while myelosuppression was mild. There were no complete responses; however, two minor responses were observed. The pharmacokinetics of didemnin B were studied in 10 patients who received the drug as 30 to 60 min i.v. infusions. A sensitive competitive inhibition enzyme immunoassay was used to quantitate didemnin B levels. Drug was observed to be rapidly cleared from plasma in a biphasic manner (t1/2 alpha = 0.12 hr, t1/2 beta = 4.8 hr). Although the assay could not identify the presence of specific metabolites, the increase of apparent didemnin B levels in plasma at later time points suggested the formation of unidentified metabolites which cross reacted with the antibody in the analytical procedure. In vitro experiments indicated that didemnin B was not bound to bovine serum albumin and only a minor portion (24%) of drug was found associated with red blood cells.
Adult↗
Isolation of sesbanimide from the seed of Sesbania vesicaria.
1. The HPLC separation of a water-soluble toxic fraction isolated from the seed of Sesbania vesicaria provided a potent antileukemic compound which was identified as sesbanimide (or sesbanimide A). The identity was established by comparison of the proton magnetic resonance spectra of the isolated sesbanimide and the authentic sample. 2. The IC50 value determined by the activity against the growth of murine leukemia (L1210) cells in vitro was 0.8 ng/ml.
Alkaloids↗
Clinical pharmacokinetics of ifosfamide in combination with N-acetylcysteine.
The pharmacokinetics of ifosfamide were studied in 20 patients with soft tissue and bone sarcomas. Drug was administered as a 30-60 min i.v. infusion at 1.2 or 2.0 mg/m2/day for five consecutive days. Some patients also received 1.5 g/m2 of N-acetylcysteine (NAC) administered 3 times per day during the course of therapy. NAC had no effect on ifosfamide pharmacokinetics. There were significant differences in plasma half-life, area under the concentration-time curve and plasma clearance on day 1 versus day 5 of ifosfamide administration. Myelosuppression and granulocytopenia correlated better with day 1 versus day 5 ifosfamide pharmacokinetics suggesting that the alteration of ifosfamide pharmacology with multiple dosing has a significant effect on drug activity.
Acetylcysteine↗