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Biomedical subjects

B Barlogie

Publications and source records attributed to B Barlogie.

At least 253 records · Page 14Linked to original sources
PubMed1982

Ploidy, proliferative activity and estrogen receptor content in human breast cancer.

Tumor samples from 80 patients with breast cancer (43 primary, 37 metastatic) were analyzed for ploidy and proliferative activity using DNA flow cytometry. Sixty-one tumors (40 primary, 21 metastatic) were also analyzed for estrogen receptor content. Eighty-five percent of all tumors had an abnormal DNA content. The majority of tumors were hyperdiploid (65%). Seventy-three tumors had a unimodal ploidy distribution, while in seven cases two distinct aneuploid subpopulations were identified. The degree of ploidy abnormality was not related to extent of disease or menopausal status, but was higher (DNA index greater than 1.5) in poorly differentiated tumors (p = 0.05). ER-positive tumors were more often diploid (7 of 31) than ER-negative tumors (3 of 30, p = 0.16). DNA content was constant in biopsies from multiple sites in 5 patients with metastatic disease and in serial biopsies over the course of the disease. High proliferative activity (percent cells in S-phase) was more often associated with ER-negative tumors than ER-positive tumors (p = 0.03). However, in all subgroups analyzed a wide range of values was noted. We conclude that flow cytometric analysis of cellular DNA content provides a rapid means of quantitating ploidy and proliferative activity in human breast cancer. Ploidy abnormalities were common, stable, and usually unimodal. Proliferative activity was inversely related to estrogen receptor content.

Aneuploidy↗
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

Ultrasound-induced hyperthermia for the treatment of human superficial tumors.

Ultrasonic systems were developed for the treatment of superficial human tumors, generating local tumor hyperthermia at tumor center temperatures ranging from 43 degrees to 50 degrees. Twenty-eight patients with disease of varying histology were evaluable for response, and demonstrated an overall response rate of 57% with a complete response rate of 18%. In 11 patients who had received definitive radiation therapy to the heat treated area, the response rate was 81%; there were no toxicities other than those noted for the overall study. As temperature was escalated a marked increase was observed both in response rates (from 53% (43-44 degrees C) to 83% (48-50 degrees C) and in duration of response (from 29 to 250 days for the same temperatures). Toxicities were minimal, consisting of superficial blistering in four patients and pain in six patients. Pain was usually associated with tumor involvement in the periostium.

Adult↗
PubMed1982

Combined ultrasound and radiation therapy treatment of human superficial tumors.

Ultrasound, used to generate local tumor hyperthermia, was combined with radiation therapy in a pilot study to determine efficacy and toxicity of this combined-modality therapy. Twenty-one lesions in eighteen patients were treated at graded doses from 2400-4000 rads (24-40 Gy) with ultrasonic hyperthermia administered immediately prior to irradiation at 43.5 degrees C +/- 0.5 degrees C for one hour. The overall response rate was 100%, with a 62% complete response rate. Of those lesions that responded completely and were followed for periods of three to twenty-two months, there have been no recurrences of the lesions treated with the combined modalities. The response rate for control unheated lesions in the same patient in the same radiation field was markedly lower (30% overall and no complete responses). Heat treatment alone in the same patients also showed lower response rates (50% overall and 10% complete) with a short response duration. Toxicities were minimal, consisting of one case with long-term treatment-associated sequelae. It is concluded that this combined modality of therapy is safe and effective where applied in human superficial tumors and that further development is warranted.

Hot Temperature↗
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

Metastasizing malignant juxtaovarian tumor with terminal hypercalcemia: a case report.

A juxtaovarian tumor of probable mesonephric origin in an 18-year-old white woman recurred six years later with a pelvic mass and widespread peritoneal metastases. Chemotherapy with cyclophosphamide, Doxorubicin, and cis-platinum induced a partial response of approximately one year duration. The terminal disease course was associated with hypercalcemia and disseminated intravascular coagulation. At autopsy, there were extensive abdominopelvic tumor masses with pleural deposits.

Adult↗
PubMed1981

Marrow cell kinetics in patients treated with methotrexate and citrovorum factor.

Methotrexate (MTX) was administered by continual intravenous infusion for 24 hours in doses ranging from 200-800 mg/m2 to 16 patients who had metastatic cancers and normal bone marrows and 11 patients with acute leukemia. Citrovorum factor (CF) was administered every 6 hours for 12-15 doses beginning 36 hours after the start of the MTX infusion. Plasma and urine were collected to measure MTX concentration. Daily bone marrow aspirates were obtained for measuring intracellular MTX concentration, labelling index (LI), mitotic index (MI), grain count distribution, cellular DNA distribution by flow cytometry (FCM), and marrow morphology. The plasma MTX concentration proved to be a function of dose and creatinine clearance. There was a positive correlation between the creatinine clearance and MTX clearance. The intracellular MTX concentration correlated highly with the plasma concentration. The LI, grain count, and proportion of cells in S phase increased on days 2 and 3. The magnitude of the changes on days 2 and 3 was dose related. The MI fell on day 2 and recovered by day 4. Transient megaloblastic changes occurred. The cell cycle perturbations in leukemic marrow were less pronounced than those in normal marrows. These observations are consistent with a transient, dose related, S phase delay.

Acute Disease↗
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

Flow cytometry and cytomorphology in primary resectable breast cancer.

Using flow cytometry for DNA analysis, ploidy and proliferative activity were measured in 43 cases of primary resectable breast cancer, 24 of which were also assayed for estrogen receptors. Tumors were studied histopathologically by multiple samples and cytopathologically by means of imprint smears and pepsinized cell suspensions. Cytologic preservation was far superior in imprint smears than in cell suspensions or histologic sections. As determined by the DNA index (tumor G1/G0:normal G1/G0), 72% of the tumors were aneuploid, with the majority falling between diploid and tetraploid. There was no correlation of ploidy with tumor cell proliferation expressed as percentages in the S-phase. A high percentage of S-phase cells was associated with estrogen receptor negativity and tended to correlate with cytologic atypia but showed no correlation with UICC stage, menopausal status, tumor size, lymph node involvement or histologic degree of malignancy. In contrast, ploidy showed no correlation with any of the above parameters but served as a reliable marker for individual tumors since it did not change with time in multiple biopsies of the primary site.

Adult↗
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↗