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Biomedical subjects

T E Moon

Publications and source records attributed to T E Moon.

At least 55 records · Page 3Linked to original sources
PubMed1984

Relation of in vitro colony survival to clinical response in a prospective trial of single-agent chemotherapy for metastatic melanoma.

We have used the effect of therapeutic agents on clonogenic growth in agar to discriminate between active and inactive agents for malignant melanoma. We report a prospective study of single-agent chemotherapy for metastatic melanoma. Forty-five separate in vitro/in vivo correlative trials were conducted in 34 patients. A number of agents were used in these evaluations, including actinomycin D, Amsacrine, bisantrene, mitoxantrone, BCNU, vinblastine, vindesine, 5-fluorouracil, MGBG, etoposide, interferon, tamoxifen, and 13-cis-retinoic acid. At the "cut-off" concentration, a colony survival less than 30% was designated as "sensitivity" and greater than 30% as "resistance." Clinical sensitivity was designated to include complete, partial, and mixed responses and was predicted in eight of 18 trials (44%). Clinical resistance (nonresponse) was predicted correctly in 24 of 27 cases (89%). Using Fisher's exact test the association of in vitro and in vivo results was significant (P = .05). These results offer further support for the concept that clonogenic assays may help select useful agents for clinical trials in metastatic melanoma.

Antineoplastic Agents↗
PubMed1984

Double-blind crossover study of the antiemetic efficacy of high-dose dexamethasone versus high-dose metoclopramide.

Nausea and vomiting remain common and debilitating side effects of therapy with many anticancer drugs. Recent reports have shown that both metoclopramide and dexamethasone are effective drugs for the treatment of severe nausea and vomiting caused by cis-platinum. A double-blind crossover study comparing the antiemetic properties of high-dose oral and intravenous regimens of metoclopramide and dexamethasone in outpatients was carried out. Standardized patient questionnaires and interviews were used to evaluate response. Dexamethasone and metoclopramide protected against more than five episodes of emesis in 48% and 40% of patients, respectively. Nausea persisted for less than six hours in 45% of patients on dexamethasone and in 37% on metoclopramide. The antiemetic efficacy of both regimens was retained through repeated courses of chemotherapy. Side effects were minimal with dexamethasone; however, 33% of patients experienced unacceptable extrapyramidal side effects to metoclopramide. Patient preference was significantly in favor of dexamethasone: 70% of patients chose to continue dexamethasone compared to 22% who preferred metoclopramide and 8% who chose other antiemetics. Dexamethasone was the preferred antiemetic in this patient population due to minimal side effects.

Adult↗
PubMed1984

Plasma kinetics of oral retinol in cancer patients.

Concurrent with a phase I trial of retinol in patients with advanced cancer, we studied the plasma kinetics of both retinol and its major metabolites, retinyl palmitate and retinyl stearate. Retinol was administered to 12 patients in daily oral doses of 60,000, 100,000, 150,000, or 200,000 units/m2. Patients remained on treatment until the development of dose-limiting toxic effects or disease progression. Retinoid plasma kinetics were studied on the first day of treatment, at Weeks 2 and 4, and every 2-3 months thereafter as long as the patient remained on therapy. A high-performance liquid chromatography assay was used to quantitate the plasma concentration of both retinol and its fatty acid esters. There was no significant change in the plasma retinol concentration up to 24 hours after a single oral dose of retinol (P greater than 0.05). However, the plasma concentration of retinyl palmitate and retinyl stearate markedly increased with a mean time to peak plasma concentration of 4.3 +/- 0.7 hours. Retinyl palmitate rapidly disappeared from the plasma with an initial phase half-life of 2.2 +/- 0.9 hours. The terminal phase half-life appeared prolonged and could not be accurately determined. Retinyl stearate was detected in the plasma of all patients with plasma concentrations paralleling and ranging from 20% to 40% those of retinyl palmitate. With prolonged retinol administration, peak plasma retinyl palmitate concentrations increased with both increasing retinol dose (P less than 0.001) and increasing duration of treatment (P = 0.001). In three patients with low pretreatment plasma retinol concentrations, daily retinol administration was associated with a rise in plasma retinol concentration. Because only one patient developed serious toxic effects and all patients had markedly increased plasma concentrations of retinyl esters, no conclusion could be made about the relationship between plasma retinyl ester concentration and retinol toxicity.

Administration, Oral↗
PubMed1984

Quantitation of the number of cells within tumor colonies in semisolid medium and their growth as oblate spheroids.

The number of cells within tumor colonies has not been determined accurately in prior reports because, in all but small clusters, cells grow too closely and stacked to allow direct counting of cells by inverted microscopy. Therefore, we stained colonies formed in agar from 38 tumor cell samples of diverse histological origin, removed them with a micropipet, and directly counted the number of cells. The number of cells within colonies increased geometrically with colony diameter and inversely with the size of the cells within the colonies. The relationship can be described using linear regression: [In(no. of cells/colony) = 0.87 - 2.80 In (colony cell diameter) + 2.38 In (colony diameter)] which gave an R2 of 0.92. Measurements of colonies in agar showed that they grew as oblate spheroids rather than spheroids. In an average sample, 60-micron-diameter colonies contained eight to 10 cells; the range for the 38 samples was 1.2 to 48.5. These results precisely define colonies in terms of cell number. They allow calculation of the total number of cells formed from clonogenic cells, a more complete estimate of proliferation than conventional cloning efficiencies which only measure initial proliferation. Furthermore, because of the dependence on the size of the colony cells, if colonies are defined only by a specific diameter then they do not contain similar numbers of cells. Calculations which assume spherical colonies, rather than the oblate spheroid shape we found, greatly overestimate the number of cells within colonies. Our data can increase the accuracy of quantitation in the clonogenic system and thus improve the interpretation of the proliferation of clonogenic tumor cells.

Cell Count↗
PubMed1983

Tumor growth stimulation in vitro by interferons.

Interferons (IFNs) are a family of polypeptides originally identified as antiviral substances. Subsequently, other properties of interferons were recognized, including inhibition of cell proliferation, and effects on the immune response and on expression of surface antigens. In this paper we present evidence that interferons, even the highly purified cloned IFNs, can stimulate clonogenic tumor growth in vitro. Of 225 human tumor (HT) samples tested with IFN in a clonogenic assay (HTCA), 30 (13.3%) showed growth stimulation (greater than 2 S.E. above control). The phenomenon was observed most frequently with acute myeloid leukemia (6/22 samples, 27.3%), and renal (2/10, 20%) and breast cancer (4/21, 19%), but significantly less frequent in melanomas (2/34, 5.9%). As an independent assessment of proliferation, tritiated thymidine uptake by tumor cells was measured autoradiographically in 21 patients with multiple myeloma. A significant increase of the thymidine labeling index was seen in 4 (19%) of the samples. Since this growth stimulatory effect was also observed with cell lines which lack any contaminating immunoreactive cells, there is strong evidence that interferons can directly stimulate the proliferation of clonogenic tumor cells in vitro. Growth stimulation by interferons occurred preferentially with lower dosages. It is important to be cognizant of potential clinical implications of tumor growth stimulation by interferons.

Cell Division↗
PubMed1983

Vitamin A: evidence for its preventive role in human cancer.

Both the provitamin beta-carotene and natural vitamin A and its derivatives (the retinoids) are being proposed as potential chemopreventive agents. The biochemistry and pharmacology of vitamin A suggest a number of mechanisms whereby carcinogenesis can be affected. Epidemiologic studies have consistently demonstrated an increased relative risk of cancer for people with low vitamin A intake or low-to-normal serum retinol values. Chemoprevention trials in humans are only now beginning. In the interim, daily consumption of vitamin-A-containing foods may be a "prescription" worth following.

Carotenoids↗
PubMed1982

Adjuvant treatment of node-positive breast cancer with adriamycin-cyclophosphamide with or without radiation therapy: interim results of an ongoing clinical trial.

During 1974-1980, 138 women with node-positive stage II breast cancer were treated with either eight courses of adriamycin-cyclophosphamide (AC) chemotherapy (82 patients) or AC chemotherapy plus comprehensive regional radiotherapy (56 patients). The overall relapse-free survival of the treated patients was significantly superior (P less than 0.001) to a comparable group of women who underwent surgery alone. This effect of adjuvant therapy was clearly manifest in all groups of patients irrespective of nodal involvement or menopausal status. To date, relapse-free survival for patients receiving AC compared to AC plus radiotherapy is not different (P = 0.7). In summary, wer have demonstrated that a brief 6-month course of adjuvant chemotherapy with AC can significantly reduce the recurrence rate in women with stage II breast cancer.

Adult↗
PubMed1982

In vitro chemosensitivities of human tumor stem cells to the Phase II drug 4'-(9-acridinylamino)methanesulfon-m-anisidide and prospective in vivo correlations.

A potential application of the human tumor stem cell colony assay is to guide Phase II clinical investigations by identifying classes of tumors (or individual patients) which are sensitive in vitro to a new antitumor compound. We have tested human tumor stem cells from 140 tumor biopsies representing 20 different tumor types for chemosensitivity to the Phase II drug 4'-(9-acridinylamino)methanesulfon-m-anisidide. In vitro sensitivity was defined as a reduction in the number of tumor colony-forming cells to 30% of the control or less after a 1-hr exposure to one-tenth of the pharmacologically achievable plasma concentration of 4'-(9-acridinylamino)methanesulfon-m-anisidide. In vitro sensitivity was found in 29 cases: non-Hodgkin's lymphoma (2 of 2); cervical carcinoma (1 of 1); sarcoma (3 of 6); neuroblastoma (1 of 2); acute myelogenous leukemia (6 of 16); chronic myelogenous leukemia (1 of 3); melanoma (8 of 34); uterine carcinoma (1 of 5); lung carcinoma (1 of 9); ovarian carcinoma (4 of 36); and breast carcinoma (1 of 11). Prospective in vitro-in vivo correlations in eight patients with various tumor types showed that three of three patients sensitive in vitro to 4'-(9-acridinylamino)methanesulfon-m-anisidide responded in vivo, while five of five patients resistant in vitro had no clinical response. The results provide support for further evaluation of the utility of the human tumor stem cell colony assay for targeting Phase II clinical trials.

Aminoacridines↗
PubMed1982

Correlation between amounts of cellular membrane components and sensitivity to hyperthermia in a variety of mammalian cell lines in culture.

The weight ratio of either cholesterol or phospholipid to protein contents in 7 different cell lines, growing exponentially at 37 degrees, correlates positively with increasing resistance of the cells to subsequent hyperthermic cell killing. The relative heat resistance of each cell line is derived from survival curves obtained when the different cell lines are exposed to 43 degrees. Cholesterol and phospholipid amounts in the particulate fraction correlate with survival sensitivity to 43 degrees when the values are expressed per mg protein but not when expressed per cell number. Also, cholesterol:phospholipid molar ratios and the amount of protein in the particulate fraction do not display linear correlations with sensitivity of the respective cell lines to 43 degrees-induced cell killing. The relative degree of fatty acid saturation at 37 degrees also is independent of whether cells show a higher degree of heat resistance. These data suggest that lipid (both cholesterol and phospholipid):protein weight ratios correlate with increasing resistance of cells to an elevation in temperature. The major implication of these data is that major membrane components can influence and perhaps predict cellular survival to hyperthermia.

Animals↗
PubMed1981

Immunocompetence and malignant lymphoma: immunologic status before therapy.

One-hundred-eighty-six previously untreated patients with malignant lymphoma were evaluated for immunocompetence by means of several tests of immune function: total circulating lymphocytes, T cells (E-rosettes), B cells (EAC-rosettes), delayed hypersensitivity to six recall antigens, serum immunoglobulins, mixed lymphocyte culture, and lymphocyte mitogenic response to phytohemagglutinin and pokeweed mitogen. The results were correlated with histology, stage, and clinical features. Diffuse lymphomas, especially diffuse histiocytic (large cell) (DHL), were associated with decreased absolute lymphocytes and E-rosette forming cells. Skin test reactivity varied with both histology and stage. For example, only one of six tests was impaired in diffuse lymphocytic well differentiated (DLWD) lymphoma in contrast to two of six in localized DHL and five of six in advanced DHL. Patients with nodular lymphoma exhibited depressed mean levels of IgA and IgG, while only IgA was significantly decreased in diffuse lymphoma. Mitogen stimulation was depressed in all groups, although mixed lymphocyte cultures did not differ significantly from controls. In summary, there is a spectrum of immunodeficiency of both B and T cell type in patients with malignant lymphoma that correlated with histology and stage. Implications and possible mechanisms of these observations are discussed.

Adult↗
PubMed1981

Malignant melanoma in southern Arizona. Increasing incidence and sunlight as an etiologic factor.

This study demonstrated an increasing incidence of malignant melanoma during the past ten years and a very high incidence of this tumor in southern Arizona. During the ten-year period, 533 melanomas were removed from white patients. Of these, 52% were male and 48% were female. The number of melanomas increased yearly, from 20 in 1969 to 120 in 1978, a crude rate incidence of 6.49 to 28.57 (27.20 standardized) per 100,000, respectively. This reflects an average annual increase of 34% to 37% and a 340% increase for the period. The highest incidence of tumor was in the 50 to 59 year and 60 to 69 year age groups. The most common site of occurrence was the back, with twice as many tumors arising there in males. The legs were involved in 13% of patients, with an occurrence rate eight times higher in females. The extremely high incidence of melanomas in southern Arizona is probably due to meteorologic and geographic factors allowing large amounts of ultraviolet light to reach the earth's surface.

Adolescent↗
PubMed1981

Quantitative association between the in vitro human tumor stem cell assay and clinical response to cancer chemotherapy.

Objective methods have been developed to quantitate results of the in vitro human tumor stem cell assay, the degree of the association between the in vitro assay and clinical response as well as the likelihood of response. Methods considered to quantitate in vitro assay data included first-order kinetics of percent survival with drug concentration, minimal percent of tumor colony-forming unit survival at low drug concentrations, and area under the in vitro percent survival-drug concentration curve. Based upon experimental data, the percent tumor colony survival and the area under the curve (i.e., in vitro sensitivity indices) were concluded to better account than other methods for the commonly observed nonlinear shape of the in vitro curves. The two methods also yielded equivalent quantitative descriptions of the in vitro data. A logistic regression model was used for explicit quantitation of the relationship between the in vitro sensitivity index and predicted probability of clinical response. Very high association was observed between the predicted in vivo and actual clinical response for the cytotoxic drugs considered. Incorporation of other pharmacologic and patient prognostic factors into the quantitative methods is discussed and shown to improve their effectiveness.

Antineoplastic Agents↗
PubMed1981

Pharmacologic studies of anticancer drugs with the human tumor stem cell assay.

To optimize the human tumor stem cell assay (HTSCA) for clinical and research purposes we have carried out in vitro pharmacology studies. Useful observations were made in four areas. (1) Drug assay design: The predictive accuracy of the HTSCA depends on the in vitro testing of drug concentrations of less than 10% of those which are pharmacologically achievable with standard in vivo drug doses. The use of unrealistically high in vitro concentrations can accurately predict clinical drug resistance, but is likely to yield high false-positive rates of clinical response prediction. (2) Drug scheduling: For certain schedule-dependent drugs, as well as those with a prolonged plasma half-life and those used according to a repeated daily schedule, prolonged in vitro exposure (rather than 1 h) may be needed to provide an adequate in vitro design. For an accurate prediction of sensitivity of tumor colony-forming units (TCFUs) to continuous drug contact in the agar, concentrations should be in the range of 1/300 that used for the standard 1-h exposure prior to plating. (3) Drug combinations: In preliminary studies of combination chemotherapy in vitro we commonly observed at least additive effects with low doses of cis-platinum plus either vinblastine or adriamycin. (4) Drug bioactivation: Rat liver microsomes or S-9 fraction were used to activate cyclophosphamide for in vitro effect, and satisfactory dose-response curves were observed for the inhibition of TCFUs. Such pharmacologic studies will be required for a wide variety of standard and new agents and will probably become a regular aspect of investigation of new anticancer drugs.

Antineoplastic Agents↗