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Biomedical subjects

J E Harris

Publications and source records attributed to J E Harris.

At least 91 records · Page 5Linked to original sources
PubMed1991

Impaired tumoricidal function of alveolar macrophages from patients with non-small cell lung cancer.

The capacity of alveolar macrophages and peripheral blood monocytes from patients with non-small cell lung cancer to develop tumoricidal function after in vitro stimulation with different macrophage activators was investigated. Alveolar macrophages were found to be impaired in their ability to develop cytotoxic activity compared with either the peripheral blood monocytes from the same patients or alveolar macrophages from patients with nonmalignant lung disorders. This result was observed consistently under diverse culture conditions and with different macrophage activators including gamma-interferon (gamma-IFN), granulocyte-macrophage colony-stimulating factor (GM-CSF), phorbol myristate acetate, or endotoxin. The impairment in tumoricidal function observed in alveolar macrophages was not associated with reduced target cell binding compared to peripheral blood monocytes. Alveolar macrophages from patients with lung cancer were found to secrete significantly greater amounts of tumor necrosis factor (TNF) and interleukin-1 (IL-1) than either peripheral blood monocytes from the same patients or alveolar macrophages from the patients with nonmalignant disorders. These results are consistent with either different regulatory pathways for cytotoxicity and cytokine secretion in the alveolar macrophages of patients with lung cancer or diversity in the subpopulations of cells responsible for these functions.

Carcinoma, Non-Small-Cell Lung↗
PubMed1991

A pilot study of three sequential chemotherapeutic regimens in metastatic breast cancer.

The aim of this pilot study was to estimate the toxicity and response rate of an alternating chemotherapeutic program in chemotherapy-naive metastatic breast cancer patients. Treatment consisted of regimen A (given days 1-28): cyclophosphamide 100 mg/m2 PO days 1-14, doxorubicin 30 mg/m2 i.v. days 1 and 8, and 5-fluorouracil 500 mg/m2 i.v. days 1 and 8 (CAF regimen); regimen B (given days 29-56): dibromodulcitol 135 mg/m2 p.o. days 30-39, mitoxantrone 9 mg/m2 i.v. day 29, and vincristine 1.2 mg/m2 i.v. (maximum 2.0 mg) day 29 (DMV regimen); and regimen C (given days 57-84): thiotepa 12 mg/m2, doxorubicin 45 mg/m2 and vinblastine 4.5 mg/m2 all i.v. on day 57. There were 27 eligible patients with a median age of 51 years (range 34-78). On 14 episodes the leukocyte count fell to less than 1 X 10(9)/L during the first six cycles of treatment (14% of 99 cycles). There were no treatment-related deaths. Common non-life-threatening toxicities included thrombocytopenia, anemia, vomiting, and alopecia. Despite having no drugs in common, the leukocyte and platelet nadirs after CAF correlated with the nadir counts after DMV (r values of 0.6829 and 0.5892, respectively; p = 0.01). Among the 23 patients with measurable and/or evaluable disease there were five complete responses (22%) and nine partial responses (39%), with a median time to treatment failure of 29 weeks. The overall median survival was 19 months.

Adult↗
PubMed1991

Vinblastine fails to improve response of renal cancer to interferon alfa-n1: high response rate in patients with pulmonary metastases.

One hundred sixty-five patients were randomized to receive either interferon alfa-n1 (Wellferon; Burroughs Wellcome Co, Research Triangle Park, NC) alone or with vinblastine. An initial six-cycle induction treatment consisted of interferon given at daily doses of 3, 5, 20, 20, and 20 x 10(6) U/m2 every 2 weeks. Vinblastine at a dose of 10 mg/m2 (later decreased to 5 mg/m2) was given on day 1 of alternate cycles. Toxicities were generally well tolerated. The overall response rate was 10% with no significant difference between treatment arms. Survival was also not significantly different for the arms. A small subset of patients (16) with metastases only to the lungs had a high complete response (CR) and partial response (PR) rate of 44%. Responses were durable, and overall survival of this group was much better than that of the other patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Improved short-term survival of AIDS patients initially diagnosed with Pneumocystis carinii pneumonia, 1984 through 1987.

I analyzed trends in the survival of 36,847 adults who were diagnosed with acquired immunodeficiency syndrome between January 1984 and September 1987 under the pre-1987 surveillance definition of acquired immunodeficiency syndrome. For patients in whom Pneumocystis carinii pneumonia was among the first manifestations of acquired immunodeficiency syndrome, the estimated 1-year survival increased from 42.7% for those diagnosed in 1984 and 1985 (95% confidence interval, 41.5% to 44.3%) to 54.5% for those diagnosed in 1986 and 1987 (95% confidence interval, 53.7% to 55.7%). The gain in survival was observed in homosexual men and intravenous drug users of both sexes, in all age and racial groups, in all geographic regions, and in patients with and without coexisting initial diagnosis. Reduced mortality in the 3-month period immediately following the initial diagnosis of acquired immunodeficiency syndrome contributed little to the overall gain in survival. No gain in survival was seen for patients in whom P carinii pneumonia was not an initial manifestation of acquired immunodeficiency syndrome. It is unlikely that the observed improvements in survival resulted solely from errors in death reporting. Better diagnosis and treatment, particularly the introduction of zidovudine in 1986, may have contributed to the decline in mortality.

Acquired Immunodeficiency Syndrome↗
PubMed1990

The in vitro development of cytotoxicity in response to granulocyte/macrophage-colony-stimulating factor or interferon gamma in the peripheral blood monocytes of patients with solid tumors: modulation by arachidonic acid metabolic inhibitors.

The capacity of granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interferon gamma (IFN gamma) to elicit monocyte cytotoxicity in vitro in the peripheral blood monocytes of patients with solid tumors was investigated. The cytotoxicity elicited by IFN gamma was significantly reduced in cancer patient monocytes compared to normal monocytes. The cytotoxicity elicited by GM-CSF, however, was comparable between cancer patient monocytes and normal monocytes, but was lower than that induced by IFN gamma. Indomethacin, a cyclooxygenase inhibitor, significantly augmented IFN gamma-elicited cytotoxicity in cancer patient monocytes, but not in normal monocytes. In contrast, indomethacin augmented GM-CSF-elicited cytotoxicity in both cancer patient monocytes and normal monocytes. Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, was found to suppress cytotoxicity in response to IFN gamma and GM-CSF in both cancer patient monocytes and normal monocytes. The addition of leukotrienes to NDGA-treated cultures restored the development of cytotoxicity. Thus there are differences in the in vitro response of cancer patient monocytes and normal monocytes to distinct biological activators. Furthermore, these responses can be manipulated by agents that modulate arachidonic acid metabolism.

Adult↗
PubMed1990

Tumor cell mitochondrial matrix/cristae complexes as potential sites for anticancer therapy with polyunsaturated fatty acid analogues.

The consequences of incubating human cancer cells with ETYA, a competitive analogue of arachidonic acid, and the reported responses of cells cultured with polyunsaturated fatty acids indicate that polyunsaturated fatty acid analogues or their modified congeners could represent potential cytotoxic anticancer agents. The inner mitochondrial membrane and matrix may represent important targets for such agents, since they seem unusually susceptible to ETYA-induced oxidative stress.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1990

Randomized phase II evaluation of carboplatin and CHIP in advanced transitional cell carcinoma of the urothelium. The Eastern Cooperative Oncology Group.

A total of 83 patients with metastatic transitional cell carcinoma who had previously received no systemic therapy entered a randomized phase II evaluation of carboplatin and cis-dichloro-transdihydroxy-bis-isopropylamine platinum IV (CHIP), administered respectively at 400 and 270 mg./m.2 every 28 days. Among evaluable patients with measurable disease response rates were 3 of 22 (14%, 95% confidence interval 5 to 35%) for carboplatin and 4 of 25 (16%, 95% confidence interval 5 to 36%) for CHIP. Among 17 patients with evaluable but not measurable metastases (10 carboplatin and 7 CHIP recipients) there were no responses. Median survival for 64 evaluable patients was 4.8 months (5.0 months for carboplatin and 4.3 months for CHIP recipients). Independent factors prognostic for survival (p less than 0.01) were performance status (0 or 1 versus 2 or 3), liver metastases, prior radiation therapy and recent weight loss (p = 0.02). Multivariate analysis confirmed that a performance status of 2 or 3 and liver metastases were predictive of shorter survival. A total of 31% of the patients treated with carboplatin and 34% of those who received CHIP experienced severe or life-threatening myelosuppression. While the response rates with carboplatin and CHIP are modest, we believe that the characteristics of these agents indicate that they should be evaluated further.

Aged↗
PubMed1990

A scheme for classifying carcinogens.

We present a scheme for classifying chemical carcinogens according to the weight of the evidence that each substance poses a human cancer hazard. The approach represents a logical extension of and builds upon those previously developed by the International Agency for Research on Cancer, the U.S. Environmental Protection Agency, and the so-called Tripartite Group of industrial scientists. It takes into account new scientific knowledge about chemical carcinogenesis and animal models. Eight categories are presented: known human carcinogen (Category 1), carcinogenic activity in animals, probable human carcinogen (Category 2), possible human carcinogen (Category 3), equivocal evidence for carcinogenic activity (Category 4), evidence inadequate for classification (Category 5), carcinogenic activity in animals; probably not a human cancer hazard (Category 6), carcinogenic activity in animals; considered not a human cancer hazard (Category 7), evidence of noncarcinogenicity (Category 8). Evidence useful for categorization includes human studies, animal bioassays, corroborative evidence from bioassays, and mechanistic studies relevant to determining the predictivity of animal responses for human hazard. Weighing this evidence to derive a conclusion about classification is a process that requires expert judgment; it cannot now be reduced to a simple set of decision rules. However, we identify the kinds of information that can be useful in this process, and indicate how each might most appropriately be used.

Animals↗
PubMed1990

Hepatic glutathione, metallothionein and zinc in the rat on gestational day 19 during chronic ethanol administration.

Ethanol, under certain conditions, alters the metabolism of sulfur amino acids, metallothionein (MT) and zinc. If chronic ethanol administration during pregnancy decreases the availability of sulfur amino acids or Zn, this deficiency could contribute to growth retardation of the fetuses, one of the features of fetal alcohol syndrome. The purpose of this study was to discern whether chronic ethanol administration to pregnant rats alters glutathione (GSH), MT or Zn content of selected tissues of the dams and fetuses. Sprague-Dawley rats were fed from gestational days 5 to 19 either the control diet ad libitum (AF), the ethanol diet ad libitum (EF) or the control diet using the pair-feeding technique (PF). On the 19th day of gestation, total hepatic GSH was significantly lower for the EF and PF dams than for the AF dams. Hepatic MT contents were similar for the AF and EF dams, and hepatic MT content was significantly greater for the PF dams than the AF and EF dams. The three groups did not differ regarding hepatic Zn content of dams or fetuses. In summary, on the 19th day of gestation, chronic ethanol feeding of pregnant rats did not lower the maternal hepatic GSH level below that of PF dams, did not induce hepatic MT in the dams and did not prevent fetuses from achieving body weights and hepatic Zn concentrations equal to those of controls.

Animals↗
PubMed1990

Phase II trial of carboplatin in soft-tissue sarcoma.

As part of the Eastern Cooperative Oncology Group program for the assessment of new drugs in sarcomas, a Phase II trial of carboplatin was performed in patients who had received no more than one prior chemotherapy regimen. A total of 50 patients received either 400 mg/m2 or 320 mg/m2 depending on whether they had received prior radiotherapy. A response rate of 16% (95% confidence interval 6-32%) occurred in the 37 patients who had received doxorubicin as their only prior systemic therapy. Three of the six responses were complete and persisted for 7 to 34 months. In contrast none of the 13 patients who received carboplatin after initial progression on doxorubicin and subsequent progression on interferon alpha responded. The overall response rate was therefore 12% (95% confidence interval 5-24%). Toxicity was primarily hematologic, with 14 patients having Eastern Cooperative Oncology Group (ECOG) grade 3 toxicity and no grade 4 or 5 toxicities. In view of the number of complete responses, carboplatin should be studied further in untreated patients with advanced soft tissue sarcoma.

Adult↗
PubMed1990

Adjuvant trial of 12 cycles of CMFPT followed by observation or continuous tamoxifen versus four cycles of CMFPT in postmenopausal women with breast cancer: an Eastern Cooperative Oncology Group phase III study.

A prospectively controlled randomized trial to compare the adjuvant efficacy of 12 cycles of cyclophosphamide, methotrexate, fluorouracil, prednisone, and tamoxifen (CMFPT) followed by observation or a total of 5 years of continuous tamoxifen versus four cycles of CMFPT followed by observation in postmenopausal women with operable node-positive breast cancer was started by the Eastern Cooperative Oncology Group (ECOG) in 1982. In 1986 the study was modified to allow patients on CMFPT X 12 plus continuous tamoxifen to be rerandomized after completing 5 years of tamoxifen to either continue for life or to stop therapy. Patients were stratified for number of involved nodes and estrogen-receptor (ER) status and randomized to receive one of three treatments: CMFPT X 4, CMFPT X 12, or CMFPT X 12 plus continuous tamoxifen. Of 962 patients entered on the study, 803 were eligible. Life-threatening toxicity occurred in 75 and lethal toxicity in seven patients. Median follow-up is 4.1 years; 279 patients had recurrent disease. Time to relapse (TTR) is significantly longer for patients on CMFPT X 12 plus continuous tamoxifen than for CMFPT X 4 (P = .002), or CMFPT X 12 (P = 0.05). Differences between four or 12 cycles of CMFPT are not significant; relapse-free rates at 5 years are 61% for CMFPT X 12 plus continuous tamoxifen, 51% on CMFPT X 12, and 52% on CMFPT X 4. Treatment differences in overall survival are not significant. Hormone receptor status and number of involved nodes were found to be significant prognostic parameters.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

5,8,11,14-eicosatetraynoic acid inhibits PC3 DNA synthesis and cellular proliferation, in part due to its 5'-lipoxygenase activity.

5,8,11,14-eicosatetraynoic acid (ETYA), a competitive analogue of arachidonic acid reversibly inhibited human prostate PC3 DNA synthesis at 4 h. This was not due to reduced cellular viability, as judged by several criteria, and resulted in reduced cell numbers at 72 h. Several less specific inhibitors of 5'-lipoxygenase, and A63162, a highly specific inhibitor, reduced labeling of DNA with 3H-thymidine. A23187, a calcium ionophore, reduced DNA synthesis, and ETYA rapidly increased [Ca2+]i measured with the Fura II technique. Comparison of the biochemical events evoked by ETYA and A63162 should identify those required for the downregulation of DNA synthesis.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1989

Lymphokine-activated killer cell induction in tumor-infiltrating leukocytes from colon cancer patients.

Lymphokine-activated killer (LAK) cell induction was evaluated in the peripheral blood mononuclear cells (PBMC) from 28 colon cancer patients and in the tumor-infiltrating leukocytes (TIL) from 20 of the patients' colon cancer specimens. Modulation of LAK cell induction in TIL and PBMC by inhibitors of arachidonic acid metabolism also was examined. LAK cells were induced in vitro in isolated TIL and PBMC by culturing with 500 U/ml of recombinant interleukin-2 (IL-2) for 3 to 5 days, and this was followed by the assessment of cytolytic activity against natural killer (NK)-resistant Chang hepatoma cells. LAK cell induction in the TIL was depressed significantly, compared with LAK cell induction in the PBMC of colon cancer patients (P less than 0.01). In the majority of cases, indomethacin augmented LAK cell induction in the TIL (P = 0.073 for the entire group, compared with cultures not treated with indomethacin) and nordihydroguaiaretic acid (NDGA) depressed LAK cell induction (P less than 0.05 for the entire group, compared with cultures not treated with NDGA). Further characterization of the mechanisms responsible for modulating LAK cell induction in the TIL of cancer patients may identify ways to optimize their use in adoptive cellular immunotherapy.

Adult↗
PubMed1989

Inhibition of U937 eicosanoid and DNA synthesis by 5,8,11,14-eicosatetraynoic acid, an inhibitor of arachidonic acid metabolism and its partial reversal by leukotriene C4.

When replicating U937 cells were incubated with up to 80 microM concentrations of the in vitro inhibitor of eicosanoid biosynthesis, 5,8,11,14-eicosatetraynoic acid (ETYA), DNA synthesis measured by labeling with [3H]thymidine was inhibited in a concentration-dependent manner. No reduction in cellular viability occurred, as judged by exclusion of trypan blue, unaltered release of 51Cr-labeled proteins, and the reversibility of inhibition after incubation for 72 h with ETYA. Neither indomethacin nor acetylsalicylic acid, inhibitors of cyclooxygenase, altered DNA synthesis in control or ETYA-inhibited cells, excluding participation of the products of this enzyme in the inhibition of DNA synthesis. Incubation of inhibited cells with extracts prepared from log-phase media partially reversed the inhibition of DNA synthesis. Addition of leukotriene B4 or D4 at 10(-7) to 10(-8) M did not reverse ETYA-induced inhibition of DNA synthesis, nor did the addition of a series of long chain fatty acids, including arachidonic acid. However, leukotriene C4 at 10(-7) M partially reversed the inhibition of DNA synthesis. Extracts of media from log-phase cells were shown by high-pressure liquid chromatography to contain leukotriene C4, and synthesis of this compound was inhibited by ETYA, as judged by measurement of UV absorbance and radioactivity. Additional inhibitors of eicosanoid metabolism including nordihydroguaiaretic acid and esculetin also suppressed DNA synthesis in U937, K562, and prostate PC3 cells, without altered cellular viability; the effect is not limited to lymphohematopoietic cells or to a single inhibitor of arachidonic acid metabolism. Suppression of U937 DNA and eicosanoid synthesis by ETYA and the partial reversal of DNA synthesis by leukotriene C4 suggest that in these cells eicosanoids may modulate DNA synthesis. Other possible consequences of incubating cells with ETYA including creation of arachidonic acid-deficient membranes, and even incorporation of the agent into membrane phospholipids, may also contribute to the reversible inhibition of DNA synthesis.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1989

Requirements for histoplasmin presentation by accessory cells to a Histoplasma capsulatum-reactive T-cell line.

We examined the pathways involved in presentation of native histoplasmin by adherent splenocytes (as a source of accessory cells) to JC1, a Histoplasma capsulatum-reactive murine T-cell line that is CD4+. JC1 did not respond to accessory cells that had been fixed with paraformaldehyde and then exposed to histoplasmin but did proliferate to antigen-pulsed cells that were subsequently fixed. Accessory cells that were coincubated with histoplasmin and sodium azide or 2-deoxy-D-glucose failed to induce proliferation of JC1. Moreover, accessory cells exposed to the lysosomotropic agents, chloroquine and ammonium chloride, were unable to present antigen. Monensin also inhibited presentation of histoplasmin if added to accessory cells concomitant with antigen. In contrast, accessory cells that had been pulsed with antigen for 2 hr and then exposed to each inhibitor for 2 hr stimulated proliferation of JC1. The antigen-presenting capacity of accessory cells that had been pulsed with histoplasmin for 2 hr was diminished considerably by subsequent treatment with phospholipase A2. Additional studies demonstrated that cerulenin, which depresses posttranslational lipid modification of proteins, abolished presentation of histoplasmin. The reactivity of JC1 was sharply reduced by anti-L3T4 (CD4) or by anti-I-Ab monoclonal antibody. The results not only indicate that presentation of histoplasmin requires active metabolic events within accessory cells, they also delineate the pathways involved in handling this antigen.

Ammonium Chloride↗