Abnormal cellular DNA content as a marker of neoplasia.
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Aneuploidy↗
Biomedical subjects
B Barlogie
Publications and source records attributed to B Barlogie.
High-dose cytosine arabinoside in multiple myeloma.
In 14 patients with advanced refractory multiple myeloma, the effect of high-dose cytosine arabinoside (ara-C) administration was evaluated. There was one partial remission among 13 evaluable patients who received 2 g/m2 intravenously over 2 hr every 12 hr, for a total of 2-8 g/m2 per course, repeated every 3-4 weeks. Myelosuppression constituted the dose-limiting toxicity, causing two treatment-related deaths from infection and bleeding. Prior extensive therapy, a low percentage of cells in S phase and low levels of intracellular ara-CTP accumulation in the bone marrow could explain the resistance of myeloma to this treatment.
Aged↗
In vitro suppression of DNA synthesis by a remission induction agent and its correlation with response in adult acute leukemia.
Fifty-three adult patients who presented with previously untreated acute leukemia had leukemic cells incubated in vitro with five doses of cytosine arabinoside (0.001-0.1 microgram/ml) and adriamycin (0.1-10 microgram/ml). Thymidine incorporation was measured in treated and untreated cells. Greater than 80% suppression of pretreatment thymidine incorporation after treatment with 0.004 micrograms/ml of cytosine arabinoside correlated with complete remission (CR) of the patient. A Mahalanobis' D2 score, which provides an index of the deviation of patient's in vitro drug response from the mean profile of responders, was calculated for each drug. Patients who had D2 values greater than 10 for Ara-C were less likely to respond to therapy. Patients with low D2s had rates of CR higher than predicted by the prognostic model employed at U.T.M. D. Anderson Hospital. However, unlike in our previous report, responders and non-responders were not clearly separable on the basis of the D2 value.
Adolescent↗
Cultured human tumour cells may be arrested in all stages of the cycle during stationary phase: demonstration of quiescent cells in G1, S and G2 phase.
Six human colon carcinoma cell lines were induced to enter stationary phase of growth by nutrient deprivation and cell crowding. Growth kinetics parameters (cell number, flow cytometric analysis of DNA distribution, and labelling and mitotic indices) were measured sequentially for all lines during the various stages of in vitro growth. Our results demonstrated that a substantial fraction of cells (9-18%) were located in G2 phase when they changed from an exponential to a stationary mode of growth. Moreover, a large number of cells in stationary phase of growth had an S-phase DNA content, as determined by flow cytometry, but failed to incorporate radioactive DNA precursors (up to 15-fold difference). To substantiate these findings, cells in stationary phase of growth were induced to enter exponential growth by re-seeding in fresh medium at a lower density. Subsequently observed changes in DNA-compartment distribution, and in labelling and mitotic indices were those expected from cells that had been arrested at different stages of the cycle during their previous stationary phase. Thus, the non-proliferating quiescent state (Q), traditionally located 'somewhere' in G1 phase, appears to be composed also of cells that can be arrested at other stages of the cycle (Qs and QG2). Although the proportion of such cells is rather small, their contribution to the growth kinetics behaviour of human in vivo tumours will become apparent following 'recruiting' or 'synchronizing' clinical manoeuvres and will prevent the formation of a clear-cut wave of synchronized cells.
Cell Cycle↗
Flow cytometry in cancer diagnosis.
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Antibodies, Monoclonal↗
Cellular discriminants for a biological classification of human colon carcinoma.
We categorized established human colon carcinoma cell lines into three biological groups. Our studies were performed on six colorectal cancer lines representing the proposed three groups. Group I consisted of two lines designated LoVo and SW 48; Group II comprised two lines called SW 480 and SW 620; and Group III was represented by lines SW 403 and SW 1116. Group I consisted of the most differentiated cells. This differentiation encompassed morphological markers, gland and signet ring formation, and ciliary development. The outstanding morphological characteristic of Group III was the development of numerous multinucleated giant cells. The range and modal chromosome number increased from Group I to Group III, a change reflected by the higher DNA content of these cells as measured by flow cytometry. Carcinoembryonic antigen synthesis was maximal for Group III and virtually absent for Group II. The number of clonogenic cells decreased from Group I to Group III, while the proportion of nonproliferating cells calculated both by experiments using continuous labeling with tritiated thymidine, and by the primer-available alpha-DNA polymerase index, increased from Group I through Group III. Another important cytokinetic difference was that Group I had an exponential cell cycle stage distribution not seen for the other groups. Cells in Group I were easily propagated in athymic (nude) rats by s.c. injection; cells in Group II injected s.c. grew for about 30 days and then regressed spontaneously. Cells in Group III could only be grown when inoculated intracerebrally. Thus, our studies have now confirmed and extended the hypothesis that cultured human colorectal carcinomas can be separated into at least three groups on the basis of morphological differentiation, chromatin distribution, carcinoembryonic antigen production, cytokinetic properties, and xenograft propagation. Perhaps this classification is just the tip of the iceberg, and future studies will determine the existence of additional groups or subgroups on the basis of other markers. However, at present it appears established that malignant cells with a common histological origin in the gut express their phenotypic potential in a sufficiently discrete manner as to permit their classification into distinct biological groups. Thus, the stage is set for extrapolating this in vitro classification for an in vivo segregation of human colorectal tumors into categories with specific properties and diverse prognosis.
Animals↗
Analysis of pleural effusions using automated flow cytometry.
Flow cytometry allows rapid and accurate analysis of the deoxyribonucleic acid (DNA) content of a large number of cells. In solid tumors, the presence of aneuploidy has been shown to correlate wall with the presence of neoplastic cells. Both cytologic examination and DNA analysis by flow cytometry were performed on pleural effusions from 33 patients. Results of the two examinations were in agreement in 10 of 12 malignant pleural effusion (two false-negatives) and in 20 of 21 benign effusions. One patient with cirrhosis, ascites and Nocardia pneumonia had hypodiploid cells (false-positive) in the pleural fluid. All patients who had a malignancy, but whose pleural effusion proved to be due to a benign cause, had cells with normal DNA content in their pleural effusion. DNA analysis using flow cytometry can be rapidly performed and is highly specific and sensitive. The finding of hyperdiploid cells is highly suggestive of malignancy.
Adult↗
Anaplastic myeloma with massive extramedullary involvement. Report of two cases.
Two patients developed anaplastic myeloma associated with prominent extramedullary disease one and four years after the initial diagnosis of multiple myeloma. Most tumor cells in the extramedullary sites were primitive-appearing and anaplastic, although plasmacytoid differentiation was evident. One patient had concurrent bone marrow involvement by cytologically similar cells, while the other patient was in bone marrow remission when he developed clinically evident soft tissue infiltration. Immunoperoxidase staining showed similar cytoplasmic immunoglobulin in both the mature-appearing and anaplastic cells in both patients. Electron microscopy in both cases showed a morphologic spectrum between the mature-appearing and anaplastic cells. DNA flow cytometric studies following the onset of extramedullary disease revealed a tumor cell population with a high degree hyperdiploid abnormality and unusually high proliferative activity in both cases, consistent with the morphologic anaplasia. Anaplastic myeloma appears to represent a distinct, aggressive variant of multiple myeloma which may result from a transformation of well differentiated myeloma cells to poorly differentiated immunoblast-like cells.
Abdominal Neoplasms↗
High-dose cytosine arabinoside (Ara-C) in colorectal cancer.
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Adenocarcinoma↗
Marrow cytometry and prognosis in myeloma.
We have previously shown that flow cytometric analysis of acridine orange-stained bone marrow cells is useful for the objective enumeration and characterization of plasma cells from patients with myeloma, frequently exhibiting an abnormal DNA and an elevated RNA content. In this report on 77 previously untreated patients, we have investigated the biologic and prognostic implications of these quantitative tumor cell parameters. The degree of marrow involvement by tumor, both by microscopic and cytometric analysis, correlated with the clinically derived tumor mass stage. Examination of the product of relative tumor cell RNA content and marrow tumor infiltrate (as a measure of metabolic capacity for immunoglobulin production) in relationship to the myeloma protein concentration in the serum revealed differences in the efficiency of immunoglobulin production and/or catabolism. There was an inverse relationship between the degree of marrow tumor involvement and RNA index, suggesting a more aggressive behavior of myeloma in patients with a low tumor cell RNA content. Prognostically, high tumor cell RNA content identified patients with a high likelihood of response to both initial treatment (32 patients, P = 0.004) and salvage therapy (29 patients, P = 0.01). Favorable factors for survival were low clinical tumor mass stage (P = 0.07) and low marrow tumor infiltrate as determined morphologically (P = 0.04) and cytometrically (P = 0.004). Thus, the direct examination of marrow cellular DNA and RNA content permitted assessment of tumor burden and was useful in the prediction of response and survival.
Bone Marrow↗
High-dose cytosine arabinoside in non-Hodgkin's lymphoma.
Thirty-two patients with refractory non-Hodgkin's lymphoma were treated with high-dose cytosine arabinoside (ara-C) given at 2 g/m2 IV over three hours every 12 hours for 4-8 g/m2/course repeated at three to four week intervals. There were eight partial responses (29%) and two minor responses among 28 evaluable patients. The median response duration was 10 weeks (range, 6-33 weeks). The median survival was significantly prolonged in responders compared to nonresponders (28 versus 15 weeks; p = 0.03). Two additional patients treated with 12 g/m2/course died of sepsis and myelosuppression. The dose-limiting toxicity was myelosuppression, which was more pronounced in patients with prior extensive radiation therapy and bone marrow involvement. In vivo measurements of intracellular concentrations of ara-CTP, the active metabolite of ara-C, showed significantly higher values in bone marrows with lymphomatous involvement compared to normal bone marrows (210 versus 95 microM; p = 0.05), probably indicating a preferential formation and retention of ara-CTP in malignant cells compared to normal hemopoietic cells. In addition, higher ara-CTP levels were found in bone marrows that had higher percentages of cells in S phase.
Adult↗
Potentiation of DNA-reactive antineoplastic agents and protection against S-phase-specific agents by anguidine in Chinese hamster ovary cells.
Anguidine, a protein synthesis inhibitor, has been shown to induce a reversible cell cycle arrest in exponentially growing Chinese hamster ovary cells. The effect of pretreatment with anguidine on the cytotoxicity of subsequently administered various chemotherapeutic agents, hyperthermia, and radiation was investigated. We found that anguidine greatly potentiated the cytotoxic activity of cis-dichlorodiammineplatinum(II) and melphalan by abolishing the initial shoulder and steepening the subsequent exponential portion of the survival curves. Bleomycin-induced cell kill was also potentiated by anguidine pretreatment but to a lesser extent. However, anguidine pretreatment did not substantially alter radiation cytotoxicity. In contrast, anguidine markedly reduced the lethal effect of hydroxyurea, 5-fluorouracil, and hyperthermia, three modalities with S-phase activity. To investigate whether both anguidine-induced potentiation and protection of cells by different antitumor agents were due to its induction of complete suspension of cycle traverse, experiments were also conducted with plateau-phase cultures. Whereas anguidine potentiated cis-dichlorodiammineplatinum(II) cytotoxicity in an identical fashion as noted in exponentially growing cells, its protective effect against lethal damage from Adriamycin was absent. Thus, it appears that the two opposite effects of anguidine modification of cell kill by cytotoxic agents (protection and potentiation) come about by two different mechanisms, with cell cycle arrest underlying cytoprotection and the mechanism of synergistic toxicity remaining obscure.
Animals↗
Quantitative cytology in leukemia research.
A study was undertaken to determine the usefulness of flow cytometric analysis of bone marrow cells as an objective means for diagnosis, classification and prognosis in patients with leukemia. Abnormal DNA content as a marker of neoplastic disease was found in only 15% of 264 adult patients with acute leukemia (13% in AML, 26% in ALL/AUL). Alternative means of tumor cell detection in heterogeneous marrow samples include determination of nucleolar antigen density and double-stranded RNA content. Phenotypic characterization of leukemia subtypes can be afforded by RNA content analysis of acridine orange-stained cells, demonstrating significantly higher mean RNA content values in AML, compared to ALL/AUL. Cytokinetic parameters amenable to flow cytometric analysis include measurements of cell cycle compartment distribution by DNA content, of cycle traverse rate by BUdR-induced modification of fluorescence intensity of DNA specific dyes and of growth fraction employing the method of in situ DNA denaturation and subsequent acridine orange staining. Determination of cell cycle distribution and RNA content pretreatment and serially during remission induction in 82 patients demonstrated a significantly lower pretreatment biopsy S phase proportion in responding patients with AML compared to individuals failing treatment whereas an opposite trend was noted in patients with ALL/AUL. While of no prognostic impact pretreatment, serial determinations of the RNA content during the first chemotherapy induction course revealed significant differences between responding and failing patients with AML. Also, patients attaining remission demonstrated a rise in marrow biopsy S phase compartment size by day 10 to 14 of treatment, thus, predicting remission during marrow hypoplasia. We conclude that quantitative cytologic examination of marrow cells from patients with acute leukemia provides useful diagnostic and prognostic information that should aid in the stratification of patients with poor prognosis to receive new agents.
Adult↗
Flow cytometry in clinical cancer research.
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Cell Division↗
Cell cycle and effect of antineoplastic drugs: facts and pitfalls.
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Animals↗
Selective protection by anguidine of normal versus transformed cells against 1-beta-D-arabinofuranosylcytosine and Adriamycin.
Anguidine, a protein synthesis inhibitor, has been shown previously to induce a reversible arrest of cell progression through all phases of the mitotic cycle without inducing appreciable cell kill. This "frozen" cell cycle state provided protection of Chinese hamster ovary cells against the lethal effects of 1-beta-D-arabinofuranosylcytosine, Adriamycin, hydroxyurea, 5-fluorouracil, and hyperthermia. We now report on the preferential induction of cytostasis by anguidine in normal WI-38 fibroblasts, occurring at one-tenth of the dosage required to inhibit the cycle progression of WI-38 VA13 cells, the SV40 transformant. Pretreatment with anguidine at a concentration producing effective inhibition of normal cell cycle traverse while permitting sustained proliferation of transformed cells resulted in almost complete protection of WI-38 normal cells against the growth-inhibitory effects of 1-beta-D-arabinofuranosylcytosine and Adriamycin, without reducing the antiproliferative effects of these two agents against WI-38 VA13 transformed cells. Thus, this cytokinetic concept of preferential normal tissue protection should be explored in vivo to increase the therapeutic index of cancer chemotherapy.
Cell Cycle↗
Comparative cytotoxicity of bisantrene, mitoxantrone, ametantrone, dihydroxyanthracenedione, dihydroxyanthracenedione diacetate, and doxorubicin on human cells in vitro.
The cytotoxic efficacies of several substituted anthraquinones, ametantrone, dihydroxyanthracenedione, dihydroxyanthracenedione diacetate, mitoxantrone, bisantrene, and doxorubicin, were evaluated on an established human colon adenocarcinoma cell line by the method of inhibition of colony formation. The concentration-dependent survival curve following treatment for 1 hr was biphasic exponential for all agents. At concentrations below 1 microgram/ml, mitoxantrone was about twice as active as both hydroxyl-substituted anthracenediones and doxorubicin, about 14 times more efficacious than ametantrone, and about 22 times more powerful than bisantrene. At higher concentrations, these differences in efficacy became even more pronounced. Treatment in stationary phase decreased the lethal efficacy of doxorubicin but not that of the other agents. No recovery of potentially lethal or sublethal damage was noted for any agent, but for anthracenedione derivatives, there was a small but statistically significant increase in cell kill during fractionated exposure. Continuous treatment with mitoxantrone or bisantrene resulted in marked degrees of cell killing, reaching 99.95 and 99.5%, respectively, after 24 hr. For doxorubicin, cell kill efficacy declined after 4 hr. Mitoxantrone was 10-fold more active on cells in G2 phase than on those in mid- to late-S phase. Sensitivity in G1 phase was intermediate. Thus, mitoxantrone appears as the most active compound while bisantrene and ametantrone are the least active agents. The cytotoxic efficacy of bisantrene increases during prolonged continuous exposure, while that of mitoxantrone increases in fractionated administration. These characteristics could be exploited in clinical strategies designed to improve the performance of these agents.
Anthracenes↗
Tubular complexes of endoplasmic reticulum in lymphoblastic lymphoma: case report.
Distinctive intracytoplasmic tubular complexes have been identified occasionally by electron microscopy in a wide variety of hematologic and nonhematologic disorders. The mechanism of induction and significance of these tubular complexes are unknown. Tubular complexes were identified in the majority of bone marrow lymphoma-leukemia cells in a patient with documented lymphoblastic lymphoma in lymph node. These complexes varied in size but in general ranged from 800--1500 nm, and consisted of masses of nonparallel, twisted, smooth, 40-nm tubules. Continuity with adjacent endoplasmic reticulum was evident in some of the complexes. Cytochemical characteristics of the malignant cells included strong, focal, paranuclear acid phosphatase reactivity and strong, stippled nuclear terminal deoxynucleotidyl transferase positivity. Flow cytometric analysis showed a DNA-RNA content pattern consistent with acute lymphoblastic leukemia and typical of T-cell lymphoma. This represents the first report of such tubular complexes in a presumed T-cell malignancy.
Acid Phosphatase↗