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Biomedical subjects

J M Hamilton

Publications and source records attributed to J M Hamilton.

At least 19 recordsLinked to original sources
PubMed1995

Generation of human cytotoxic T cells specific for human carcinoembryonic antigen epitopes from patients immunized with recombinant vaccinia-CEA vaccine.

BACKGROUND: The human carcinoembryonic antigen (CEA), which is expressed in several cancer types, is a potential target for specific immunotherapy using recombinant vaccines. Previous studies have shown that when the CEA gene is placed into vaccinia virus, the recombinant vaccine (rV-CEA) can elicit T-cell responses in both rodents and non-human primates. PURPOSE: Our objective was to determine if rVCEA could elicit CEA-specific T-cell responses in humans with appropriate human leukocyte antigen (HLA) motifs. METHODS: Peripheral blood lymphocytes (PBLs) obtained from patients with metastatic carcinoma, both before and after vaccination with rV-CEA, were analyzed for T-cell response to specific 9- to 11-mer CEA peptides selected to conform to human HLA class I-A2 motifs. RESULTS: While little or no T-cell growth was seen from preimmunization PBLs of patients pulsed with CEA peptides and interleukin 2 (IL-2), T-cell lines were obtained from PBLs of patients after vaccination with one to three cycles of stimulation. Cytolytic T-cell lines from three HLA-A2 patients were established with a 9-amino acid peptide (CAP-1), and the CD8+/CD4+ double-positive T-cell line (V24T) was chosen for detailed analysis. When autologous Epstein-Barr virus (EBV)-transformed B cells were either incubated with CAP-1 peptide or transduced with the CEA gene using a retroviral vector, they were lysed by the V24T cell line, but allogeneic non-A2 EBV-transformed B cells were not. The SW403 human colon carcinoma cell line, which is CEA positive and HLA-A2 positive, was also lysed by the V24T cell line, while two non-HLA-A2 CEA-positive colon carcinoma cell lines were not. To further confirm the class I HLA-A2 restricted nature of the V24T cytotoxicity, the non-HLA-A2 SW837 CEA-expressing colon carcinoma cell line was infected with a recombinant vaccinia virus expressing the HLA class I-A2 gene, and it became susceptible to V24T lysis. Cells infected with vector alone were not lysed. CONCLUSIONS: This study demonstrates for the first time (a) the ability to generate a human cytolytic T-cell response to specific epitopes of CEA, (b) the class I HLA-A2 restricted nature of the T-cell mediated lysis, and (c) the ability of human tumor cells to endogenously process CEA to present a specific CEA peptide in the context of major histocompatibility complex for T-cell-mediated lysis. IMPLICATIONS: These findings have implications in the development of specific second-generation cancer immunotherapy protocols.

Amino Acid Sequence↗
PubMed1995

Phase I clinical trial of continuous infusion cyclopentenyl cytosine.

Cyclopentenyl cytosine (CPE-C) is an investigational drug that is active against human solid tumor xenografts. The 5'-triphosphate of CPE-C inhibits CTP synthase, and depletes CTP and dCTP pools. We conducted a phase I clinical trial of CPE-C given as a 24-h continuous i.v. infusion every 3 weeks in 26 adults with solid tumors. The starting dose rate, 1 mg/m2 per h, was selected on the basis of both preclinical studies and pharmacokinetic data from two patients obtained after a test dose of 24 mg/m2 CPE-C as an i.v. bolus. Dose escalation was guided by clinical toxicity. A total of 87 cycles were given, and ten patients received four or more cycles. The mean CPE-C steady-state plasma levels (Cpss) increased linearly from 0.4 microM to 3.1 microM at dose levels ranging from 1 to 5.9 mg/m2 per h (actual body weight); the mean total body clearance was 146 +/- 38 ml/min per m2. CPE-C was eliminated by both renal excretion of intact drug and deamination to cyclopentenyl uracil in an apparent 2:1 ratio. CTP synthase activity in intact bone marrow mononuclear cells was inhibited by 58% to 100% at 22 h compared to matched pretreatment samples at all CPE-C dose levels. When all data were combined, flux through CTP synthase was decreased by 89.6% +/- 3.1% at 22 h (mean +/- SE, n = 16), and remained inhibited by 67.6% +/- 7.7% (n = 10) for at least 24 h post-CPE-C infusion. Granulocyte and platelet toxicities were dose-dependent, and dose-limiting myelosuppression occurred during the initial cycle in two of three patients treated with 5.9 mg/m2 per h. Four of 11 patients (4 of 20 cycles) who received 4.7 mg/m2 per h CPE-C experienced hypotension 24-48 h after completion of the CPE-C infusion during their first (n = 2), third (n = 1) and sixth cycles (n = 1), respectively. Two of these patients died with refractory hypotension despite aggressive hydration and cardiopulmonary resuscitation. One of 12 patients (28 total cycles) treated with 3.5 mg/m2 per h CPE-C experienced orthostatic hypotension during cycle 1, and this patient had a second episode of orthostatic hypotension at a lower dose (3.0 mg/m2 per h). Hypotension was not seen in patients receiving < or = 2.5 mg/m2 per h CPE-C.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

Dimensions of neurobehavioural dysfunction: cross-validation using a head-injured sample.

Principal-components analysis of 44 items from the Minnesota Multiphasic Personality Inventory (MMPI) identified as neurologically related was conducted on profiles obtained from 196 individuals with head injury. Four principal factors, that accounted for 36.5% of the total variance, were extracted. The first factor was composed of items tapping attention and memory complaints. The second factor consisted of items focusing on somatic complaints. Items primarily tapping behavioural disturbance made up the third factor, and the fourth factor was composed of items reflecting specific somatic or neurological complaints. These findings partially confirmed those obtained in previous research, and further illuminate the need for developing a specific and brief measure to characterize neurobehavioural dysfunction for neurological samples.

Adolescent↗
PubMed1991

A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma.

Thirty-one assessable patients with metastatic adenocarcinoma of the gastrointestinal tract were entered onto a pilot study designed to assess the impact of recombinant interferon alpha-2a (rIFN alpha-2a) on the toxicity and pharmacokinetics of fluorouracil (5-FU) and leucovorin (LV). Patients received an initial cycle of 5-FU (370 or 425 mg/m2/d) with LV (500 mg/m2/d) for 5 days. If tolerated, the patient received the same dose of 5-FU/LV for the second cycle on days 2 to 6, with rIFN alpha-2a at 5 x 10(6) or 10 x 10(6) U/m2/d on days 1 to 7, or with 3 x 10(6) U/m2/d on days 1 to 14. In 26 matched cycles, rIFN alpha-2a administration was associated with an increased incidence of dose-limiting mucositis and diarrhea and a significantly lower median platelet nadir; rIFN alpha-2a did not significantly affect the median WBC or granulocyte nadir. Dose-limiting toxicity occurred in all six patients entered at 425 mg/m2/d of 5-FU/LV within two cycles. The majority of patients treated with 370 mg/m2/d of 5-FU/LV and 10 x 10(6) U/m2/d rIFN alpha-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 x 10(6) and 5 x 10(6) U/m2/d rIFN alpha-2a had acceptable toxicity. Administration of rIFN alpha-2a was associated with a dose-dependent decrease in 5-FU clearance. The increase in the area under the 5-FU concentration-time curve (AUC) was 1.3-fold and 1.5-fold in patients receiving 5 x 10(6) and 10 x 10(6) U/m2/d rIFN alpha-2a, respectively. Thus, the increase in 5-FU toxicity with rIFN alpha-2a may be explained by alterations in 5-FU pharmacokinetics. In 22 patients without prior 5-FU therapy, three complete (13.6%) and seven partial (31.8%) responses were seen, for an overall response rate of 45.4% (95% confidence interval, 24.4% to 67.8%). Since the 5 x 10(6) U/m2/d dose of rIFN alpha-2a increased the 5-FU drug exposure and was associated with acceptable toxicity, we recommend its further evaluation as given on days 1 to 7 in combination with 5-FU 370 mg/m2/d, with high-dose LV given on days 2 to 6.

Adenocarcinoma↗
PubMed1991

Levamisole: known effects on the immune system, clinical results, and future applications to the treatment of cancer.

Levamisole has been used in a wide array of clinical research and treatment settings over the past two decades, ranging from such diseases as helminthic infestations to various autoimmune diseases. Numerous preclinical evaluations and clinical trials with levamisole in the cancer arena have been sponsored by the National Cancer Institute and other agencies worldwide with the hopes of demonstrating anticancer activity. Trials in advanced breast cancer, lung cancer, colorectal cancer, melanoma, and lymphoproliferative diseases have generally been negative or inconclusive. However, there is some indication that levamisole may be useful by itself as an adjuvant therapy for resected melanoma; recently it has been shown to be effective in combination with fluorouracil (5-FU) as adjuvant therapy for tumor-node-metastasis (TNM) stage III (Dukes' C) colon carcinoma. In the aggregate, the past 20 years of clinical experience with levamisole has resulted in as many questions as answers. However, further testing of the anticancer activity of levamisole can be expected in clinical research trials over the next few years. Hopefully, these future trials will include studies of the mechanisms of action of this agent.

Animals↗
PubMed1991

Coping with stress.

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Adaptation, Psychological↗
PubMed1989

Surrogate endpoints in clinical trials: cancer.

Investigators use a surrogate endpoint when the endpoint of interest is too difficult and/or expensive to measure routinely and when they can define some other, more readily measurable, endpoint, that is sufficiently well correlated with the first to justify its use as a substitute. A surrogate endpoint is usually proposed on the basis of a biologic rationale. In cancer studies with survival time as the primary endpoint, surrogate endpoints frequently employed are tumour response, time to progression, or time to reappearance of disease, since these events occur earlier and are unaffected by use of secondary therapies. In early drug development studies, tumour response is often the true primary endpoint. We discuss the investigation of the validity of carcinoembryonic antigen (a tumour marker present in the blood) as a surrogate for tumour response. In considering the validity of surrogate endpoints, one must distinguish between study endpoints that provide a basis for reliable comparisons of therapeutic effect, and clinical endpoints that are useful for patient management but have insufficient sensitivity and/or specificity to provide reproducible assessments of the effects of particular therapies.

Antineoplastic Agents↗
PubMed1989

Effects of norepinephrine and denervation on brown adipose tissue in Syrian hamsters.

Daily injections of either 0.8 or 3.2 mg norepinephrine (NE)/kg for 2 wk failed to stimulate brown adipose tissue (BAT) growth, GDP binding, or cytochrome-c oxidase activity (COA) in Syrian hamsters (Mesocricetus auratus). However, a single injection of 1.6 mg NE/kg produced a small (23%) but significant acute increase in BAT GDP binding without affecting COA. Thus there is some loss of sensitivity to NE with chronic treatment in Syrian hamsters. Unilateral sympathectomy by surgical denervation of the interscapular BAT (IBAT) resulted in decreased GDP binding and COA in the denervated pad. Chronic NE treatment in hamsters with denervated IBAT only partially reversed the denervation-induced decreases in GDP binding and COA. It therefore appears that NE is not solely responsible for the maintenance and stimulation of thermogenic activity and COA in Syrian hamster BAT. Denervation of IBAT also resulted in elevated levels of lipoprotein lipase (LPL) in this tissue, a surprising finding since brown and white adipose tissue LPL activity were both stimulated by chronic NE treatment. Therefore, although NE has a stimulatory effect on LPL activity, the primary influence of the neural input to IBAT on this enzyme is inhibitory. These data exemplify dramatic differences between rats and hamsters in the mechanisms controlling BAT thermogenesis and white and brown adipose tissue LPL activity.

Adipose Tissue, Brown↗
PubMed1989

Regional differences in fat pad responses to short days in Siberian hamsters.

Siberian hamsters exhibit decreased body weight and fat after initial exposure to short photoperiods and increased body weight and fat after extended short photoperiod exposure. The purpose of the present experiments was to determine if uniform changes in white adipose tissue (WAT) pad weights and lipid metabolism correspond to these short photoperiod-induced changes in body fat. Carcass lipid content and testes and fat pad weights [retroperitoneal WAT (RWAT), epididymal WAT (EWAT), and inguinal and dorsal subcutaneous WAT, respectively] were decreased in male hamsters relative to their long day counterparts after 6 and 12 wk of short-day exposure. Moreover, EWAT and RWAT weight, EWAT specific lipoprotein lipase activity, and specific and total lipogenesis were disproportionately decreased relative to the subcutaneous fat pads. The changes in fat pad weight and metabolism were generally reversed coincident with the return to a long-day-like reproductive status after prolonged short-day exposure (24 and 30 wk). In a less detailed experiment, female Siberian hamsters had decreased body, fat pad, and uterine weights after 6 wk of short-day exposure; however, no fat pad-specific changes in weight were observed. The results of these experiments demonstrate that short-day-exposed male Siberian hamsters may be a useful model for examining mechanisms underlying fat pad-specific responses. In addition, gender appears to influence the pattern of short-day-induced lipid depletion in this species.

Acclimatization↗
PubMed1988

Lipectomy does not impair fattening induced by short photoperiods or high-fat diets in female Syrian hamsters.

Syrian hamsters (Mesocricetus auratus) exhibit seasonal fluctuations in body fat that are triggered by changes in photoperiod and/or diet. Body fat accumulates when hamsters are switched to a short photoperiod or high-fat diet. The effects of surgical reduction of adipose tissue (lipectomy) on these responses were tested in adult female hamsters. Dorsal-inguinal subcutaneous, parametrial, and retroperitoneal white adipose tissues were removed bilaterally from some hamsters, while others received sham surgery. Hamsters from each surgical group were then fed a high-fat diet for the next 12 or 30 weeks, or were exposed to a short photoperiod for 13 weeks. Restoration of previously excised pads was for the most part incomplete, yet all lipectomized hamsters fully regained total body lipid, which suggests compensatory hypertrophy in other depots. Consistent with this, we found a significant increase in the weight of the previously undisturbed axillary subcutaneous pad, but this increase was small and not sufficient to offset the deficits remaining in the regenerated pads. Thus, restoration of total body lipid mass was achieved by a general increase in deposition over all depots rather than a specific renewal of removed tissue. This ability to recover completely from lipectomy is similar to that previously reported in ground squirrels. In contrast, rats and mice are frequently unable to replace lost adipose tissue. Both hamsters and squirrels adjust their levels of body fat according to season, which may afford them an enhanced ability to recover from surgical reductions of adipose tissue.

Adipose Tissue↗
PubMed1987

Genetic association between nest building and brown adipose tissue thermogenesis in female house mice.

Mice selectively bred for either high or low levels of thermoregulatory nest building were cold-acclimated (5 degrees C) for 3 weeks without nesting material; then body weight and food intake were measured. The mice selected for low nest building (Lows) of both sexes showed lower feed efficiencies than the high nest-building mice (Highs), although their body weights were not significantly different (Table 1). This adds to a large body of evidence which suggests that nest building and feed efficiency were influenced by a common mechanism (Lacy et al. 1978; Sulzbach and Lynch 1984; Lynch et al. 1981; Lynch and Roberts 1984). Brown adipose tissue mitochondrial GDP binding and cytochrome c oxidase activity were measured in the above mice. In females, the Lows had 100% higher levels of total GDP binding than the Highs, while no difference between the lines was seen in males. Thus in the High females, lower energy expenditure through brown fat thermogenesis may account for their greater feed efficiency. In males, the genetic differences in feed efficiency must be due to differences in either thermogenesis in tissues other than brown fat, or mechanisms which reduce heat loss.

Adipose Tissue, Brown↗