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Biomedical subjects

B Drewinko

Publications and source records attributed to B Drewinko.

At least 73 records · Page 4Linked to original sources
PubMed1983

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↗
PubMed1983

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↗
PubMed1983

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↗
PubMed1982

Prognostic implications of ploidy and proliferative activity in human solid tumors.

Ploidy and cell cycle compartment distribution were measured by DNA flow cytometry in 261 patients with a variety of different tumors. Eighty-one percent of all tumors were aneuploid, and 72% were hyperdiploid. Ploidy levels spanned a wide range from hypodiploid (maximum 30% less than diploid controls) to hyperoctaploid (440% in excess of diploid controls) with a mean and median values coinciding at a near-triploid DNA content. The proportion of cells with G1 DNA content decreased with increasing hyperdiploid abnormality. While unrelated to biopsy site and to a number of host factors such as age, sex and race, both ploidy and cytokinetic parameters were markedly affected by histopathologic diagnosis. Patients with metastatic lung, breast and GI cancer had higher ploidy levels than individuals with the corresponding primary tumors. Ploidy (except for one patient) remained constant, and G1/100 proportions showed only minor variation by disease site and over a median observation time of 6 months. Prognostic factor analysis was performed in the subgroup of patients studied within 6 months from diagnosis. The adverse impact of low tumor G1/100 proportion on survival was lost as the proportional hazard analysis was extended to include diagnostic subgroups. Accounting for histopathologic diagnosis, stage of disease, ploidy, and the proportion of tumor G1/100 cells, the following sequence of adverse prognostic factors in order of their relative ranks was established: (1) absence of breast cancer (p=0.0001), (2) hypertriploid DNA index (p=0.049), and (3) presence of metastatic disease (p=0.079). Our study demonstrates that DNA content-derived information on instrinsic tumor cell features pertaining to cytogenetics and cytokinetics may provide an objective means of biologically relevant cancer classification.

Aneuploidy↗
PubMed1982

Eight-parameter automated hematology analyzers: comparison of two flow cytometric systems.

The performance of two high-speed 8-parameter automated hematology analyzers (Coulter Counter S-plus and ELT-8) were compared with that of reference instruments (Coulter Counter S Sr and Technicon Autocounter). The precision, linearity, and lack of carry-over of both instruments were superior over that of existing equipment. The especially noteworthy feature of the instruments was their excellent performance in the range of extreme values of both white blood cells and platelets. This enhanced performance, and the fact that all presently known relevant hematologic parameters can be measured by a single instrument on a single sample, make the contribution of these two flow cytometric-based instruments a significant advance in the field of automated laboratory medicine.

Autoanalysis↗
PubMed1982

Ploidy and proliferative characteristics in monoclonal gammopathies.

Measurements were performed in 143 patients with monoclonal gammopathy of the cellular substrate in the bone marrow, including analysis of DNA and RNA content and tritiated thymidine labeling index. Aneuploidy by DNA content was present in 80% of 115 patients with active multiple myeloma and in 4 of 9 patients with benign monoclonal gammopathy, but was absent in all 12 patients with myeloma in remission and in 7 individuals with Waldenström's macroglobulinemia. With regard to prognosis in multiple myeloma, a low pretreatment plasma cell labeling index of less than or equal to 1% heralded longer survival than that observed in patients with a labeling index less than 1%, independent of myeloma tumor burden and ploidy pattern, except for a subset of 17 patients with a low-degree hyperdiploid abnormality whose survival was not affected by the magnitude of the pretreatment labeling index. Thus, besides tumor burden, tumor proliferative activity and ploidy both appear to have additional prognostic importance for patients with multiple myeloma.

Cell Division↗
PubMed1982

Lethal activity and kinetic response of cultured human cells to 4'-(9-acridinylamino)methanesulfon-m-anisidine.

Cytotoxic and cytokinetic effects of 4'-(9-acridinylamino)methanesulfon-m-anisidine (m-AMSA) were studied on a cultured human colon carcinoma and on a human lymphoma (T1) cell line. Proliferating cells were more susceptible (10-fold) to the cytotoxic effect of m-AMSA than were nonproliferating cells. The agent had minimal effects on DNA synthesis. At comparable exposure doses on m-AMSA, the degree of lethal cell damage exceeded inhibition of DNA synthesis by 4-fold. Cells synchronized in different stages of the cell cycle were equally sensitive to the cytotoxic effects of the drug, although the major cytokinetic effect was a block in G2. A greater killing effect was obtained by fractionated delivery than by a comparable dose delivered at one. These results suggest that superior antitumor results may be achieved by adequately spaced low doses of m-AMSA in the treatment of sensitive human tumors.

Aminoacridines↗
PubMed1982

Growth characteristics of human colonic adenocarcinomas propagated in the Rowett athymic rat.

Two human colonic adenocarcinoma cell lines were propagated in the Rowett athymic rat. Line LoVo displayed a well-differentiated morphology and exhibited progressive growth over a 70-day observation period with a doubling time of 8.5 days throughout. No metastatic involvement was noted. Xenografts of SW 620 cells were undifferentiated and highly necrotic. These tumors grew progressively for approximately 30 days with a doubling time of 5.5 days, but over 90% of the animals exhibited a spontaneous regression with a mean time to total regression of 51 +/- 3 (S.E.) days. Animals which had rejected the SW 620 xenografts would not support the growth of either the SW 620 or LoVo xenografts when challenged a second time with inocula producing a 100% tumor incidence in control rats. No metastatic involvement was noted for the SW 620 xenografts, but the tumors frequently invaded the underlying musculature and protruded into the peritoneal cavity without producing ascites or tumor nodules at sites distant from the primary.

Adenocarcinoma↗
PubMed1981

Standardization of platelet function tests.

Methods for the standardization of several currently used platelet function tests (bleeding time, capillary fragility, platelet retention, platelet aggregation, platelet factor 3, and platelet volume profiles) are presented, Different variables than may interfere with the reproducibility of the results of each assay were identified and standardized. Using the standardized techniques, the range of normal values for each test was determined in a large population of normal volunteers and used to identify disease states by comparing patient results with those of the normal population. A format for presenting the entire profile of platelet function parameters is proposed.

Adult↗
PubMed1981

A rapid automated stathmokinetic method for determination of in vitro cell cycle transit times.

To provide a rapid method for examining cell cycle dynamics, we utilized continuous exposure of Chinese hamster ovary cells and human colon cancer cells to colcemid to block cycling cells in metaphase, suppressing re-entry into G1. Changes in cell cycle compartment distribution were monitored by DNA flow cytometry. Analysis of the rate of G2 + M compartment accumulation after addition of colcemid permitted calculation of all cycle transit parameters. These compared favorably with data in the same cell lines determined by the fraction of labeled mitoses technique. Serial assessment of DNA flow cytometry after addition of colcemid permits rapid quantitation of cycle traverse rates.

Animals↗
PubMed1981

Synergistic lethal effect of cis-dichlorodiammineplatinum and 1-beta-D-arabinofuranosylcytosine.

cis-Dichlorodiammineplatinum(II) and 1-beta-D-arabinofuranosylcytosine display a dramatic synergistic effect when tested in simultaneous combination on LoVo cells, a human colon carcinoma cell line. 1-beta-D-Arabinofuranosylcytosine alone does not induce any cytotoxicity on LoVo cells even at high concentrations but is able to increase up to 1000 times the lethal effects of cis-dichlorodiammineplatinum(II). DNA elution experiments show that 1-beta-D-arabinofuranosylcytosine increases the amount of cis-dichlorodiammineplatinum(II)-induced DNA cross-links. The possible mechanisms of this effect are discussed, and some explanations are proposed.

Carcinoma↗
PubMed1981

Reduction of 1-beta-D-arabinofuranosylcytosine and adriamycin cytotoxicity following cell cycle arrest by anguidine.

The protein synthesis inhibitor anguidine induced a frozen cell cycle state in exponentially growing Chinese hamster ovary cells, as demonstrated by serial DNA flow cytometric measurements in the absence and presence of Colcemid as a stathmokinetic agent. The minimally effective concentration of anguidine for induction of cell cycle arrest was 0.1 microgram/ml. As demonstrated by tritiated thymidine labeling index and DNA flow cytometric investigations in the presence of Colcemid, a 4-hr exposure of Chinese hamster ovary cells to greater than or equal to 4 micrograms of anguidine per ml effected a greater than or equal to 12-hr cycle perturbation at no cytotoxic expense. Preincubation of exponentially growing Chinese hamster ovary cells for 4 hr with 5 micrograms of anguidine per ml reduced the cytotoxicity from Adriamycin (1 hr; 0.1 to 10 micrograms/ml) and from 1-beta-D-arabinofuranosylcytosine treatment (18 hr; 5 to 50 micrograms/ml) by 10- to 100-fold. Further investigation of the concentration dependence and time course of this protective effect of anguidine revealed a plateau at 1 microgram of anguidine per ml and lack of protection in case of anguidine exposure subsequent to Adriamycin and 1-beta-D-arabinofuranosylcytosine treatment. Prolongation of the treatment-free interval between initial anguidine exposure and 1-hr Adriamycin treatment demonstrated partial recovery of DNA synthesis associated with some loss in cytoprotection. Our results indicate that the largely indiscriminate interference with cycle progression by anguidine under noncytotoxic conditions affords significant protection against 1-beta-D-arabinofuranosylcytosine and Adriamycin-related cytotoxicity, the degree of which appears to be related to the extent of reduction in cycle traverse rate. Thus, anguidine may serve as a useful probe to study in detail drug-induced lethal injury as a function of cycle traverse rate.

Animals↗
PubMed1981

Differential killing efficacy of twenty antitumor drugs on proliferating and nonproliferating human tumor cells.

The lethal effects of a 1-hr treatment with 20 antitumor drugs on proliferating and nonproliferating cultured human colon carcinoma cells (line LoVo) were analyzed quantitatively by the colony-forming technique. Proliferating cells were obtained from exponentially growing cultures, while nonproliferating cells were from cultures in a stationary phase of growth. The 1-hr treatment was intended to approximate serum peak levels after bolus administration. Two agents, cis-platinum and vindesine, were more effective on nonproliferating than on proliferating cells. Mitomycin C, nitrosourea, and dihydroxybisalkylanthracenedione were equally effective on proliferating and nonproliferating cells. The low lethal activity (less than 1 log) of methylglyoxal bis(guanylhydrazone), hycanthone, and vinblastine was similar in proliferating and nonproliferating cells. For most drugs (Adriamycin, rubidazone, bleomycin, maytansine, vincristine, epipodophyllotoxin, fluorouracil, hydroxyurea, methotrexate, and transplantinum) cytotoxicity was significantly less pronounced (or even totally absent) in nonproliferating than in proliferating cells. These results demonstrate the significance of cellular proliferation kinetics in determining sensitivity to antitumor therapy. Nonproliferating human cells have decreased sensitivity to most antitumor agents. An occasional agent may present increased activity to nonproliferating cells; but at best, few agents can be expected to be as effective on nonproliferating as on proliferating cells.

Animals↗