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Biomedical subjects

J Early

Publications and source records attributed to J Early.

14 recordsLinked to original sources
PubMed2000

Structure-activity relationship of alkyl camptothecin esters.

The cytotoxicity of camptothecin (CPT) esters 1-6 was measured. Like parental camptothecin, esters 2 and 3, but not 1, 4, 5, and 6, inhibited proliferation of human leukemia cells in culture and induced programmed cell death as assessed by flow cytometry studies. Exhibition of similar levels of antiproliferative activities of CPT 2 and 3 required different incubation time periods in cell cultures, with CPT and 3 requiring the shortest and longest periods, respectively. Both 2 and 3 were inactive against cells resistant to the semisynthetic CPT derivative 9-nitrocamptothecin and unable to stabilize DNA-topoisomerase I (Topo I) "cleavable complexes" in a cell-free system, suggesting that Topo I activity was required but insufficient for the mechanism of action of 2 and 3. Mouse liver homogenate converted esters to parental CPT, but the conversion rates were different with different esters. Of four tested esters in this experiment, ester 2 had the fastest conversion rate. In vivo studies showed that ester 2 had an exceptional lack of toxicity in nude mice, even at enormous doses, and demonstrated extensive activity against human breast and colon tumors grown as xenografts in immunodeficient nude mice, whereas no antitumor activity was observed for the other esters. In conclusion, ester 2 is a prodrug of the antitumor compound CPT, and it can be administered at very high doses in mice with no appearance of toxicity. This study provides a basis for further evaluation of CPT ester 2 as an investigational anticancer agent.

Animals↗
PubMed1998

Altered sensitivities to anticancer and differentiation agents in etoposide-resistant human myeloid leukemia U-937 cells.

We previously have exposed U-937 human leukemia cells to stepwise increased concentrations of the anticancer drug etoposide, and this treatment has resulted in stable sublines (termed U-937/RE) exhibiting various extents of resistance to the drug and constitutively expressing c-fms mRNA, a specific marker of monocytic differentiation. In this report, we pursued studies to show that the P-glycoprotein blocker, verapamil, partially restores sensitivity to etoposide in U-937/RE cells. Further, the U-937/RE cells exhibit differential sensitivities to compounds that induce maturation of U-937 cells, as judged by the ability to reduce nitroblue tetrazolium and by morphologic changes, and increased sensitivities to apoptosis induction by the cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) and the anticancer drugs 9-nitrocamptothecin and doxorubicin. In addition, the U-937/RE cells, xenografted in immunodeficient mice, demonstrate decreased or no ability to induce tumors. Taken together, these findings indicate that U-937/RE cells differ from the parental U-937 cells in several functional properties and can serve as models to develop protocols for treatment of human leukemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Effect of variations in calcaneocuboid fusion technique on kinematics of the normal hindfoot.

Calcaneocuboid fusion with lengthening of the lateral column of the foot has been advocated as a method of treating flatfoot deformity. This study was designed to determine how the length of the lateral column chosen or the position of the foot selected when performing this fusion affect hindfoot kinematics in normal cadaver feet. An electromagnetic tracking system was used to monitor the positions of the talus, calcaneus, navicular, and cuboid while the intact cadaver feet were moved passively and then under reproducible loads. Calcaneocuboid fusion was then performed on these feet first with the feet in neutral position and the lateral column of normal length, then lengthened 10 mm or shortened 5 mm, and then with the lateral column lengthened 10 mm and the feet positioned in plantar flexion and eversion or dorsiflexion and inversion. Kinematic measurements were made at each stage using the same loads. Fusing the calcaneocuboid joint with lengthening or shortening the lateral column and the feet in neutral position did not affect hindfoot joint motion compared with intact. Changing the position of the foot for fusion, however, resulted in significant decreases in motion in the talocalcaneal and talonavicular joints. Tibiotalar joint motion was unaffected. This study, therefore, demonstrates that when fusing the calcaneocuboid joint, attention should be paid to maintaining a neutral position of the foot.

Arthrodesis↗
PubMed1996

Isolation and characterization of an apoptosis-resistant variant of human leukemia HL-60 cells that has switched expression from Bcl-2 to Bcl-xL.

Human promyelocytic leukemia HL-60 cells treated with 8-chloroadenosine-3',5'-cyclic monophosphate (8-Cl-cAMP) undergo growth arrest and subsequently die by apoptosis. We describe here the isolation of a variant of HL-60 cells, HCW-2, which was resistant to the cytotoxic effects of 8-Cl-cAMP, but still underwent growth arrest. Thus, HCW-2 cells appeared to be altered in their ability to undergo apoptosis. HCW-2 cells were also completely refractory to the apoptotic action of cycloheximide and staurosporine, two compounds which were very potent inducers of apoptosis in the parental HL-60 cells, suggesting that the resistance to apoptosis was not unique to 8-Cl-cAMP. Western blot analysis demonstrated that the parental HL-60 cells expressed both Bcl-2 and Bax, two factors known to be intimately involved in the control of apoptosis. Surprisingly, HCW-2 cells no longer expressed Bcl-2 protein and paradoxically contained Bax protein at a level that was approximately 50-fold higher than in HL-60 cells. However, Northern and Western analyses indicated that the apoptotic suppressor gene, bcl-xL, which is not expressed in the parental HL-60 cells, was expressed in HCW-2 cells. Thus, the Bcl-2-independent resistance of HCW-2 cells to apoptotic induction is discussed in terms of the expression of bcl-xL.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Establishment of human prostate tumor xenografts in nude mice and response to 9-nitrocamptothecin in vivo and in vitro does not correlate with the expression of various apoptosis-regulating proteins.

Flow cytometry and microscopy analyses have demonstrated that 9-nitrocamptothecin (9NC) induces apoptosis in prostate carcinoma LNCaP, DU-145 and PC-3 cells grown in culture or as xenografts. 9NC induces apoptosis regardless of the ability of the cells to induce tumors following xenografting into nude mice. Detection of apoptosis by flow cytometry was preceded or accompanied by increased cell size, loss of nuclear structure and vacuolization, as the tumor regressed, but no visible chromatin fragmentation. This is the first demonstration that 9NC is curative for human prostate carcinoma xenografts in the nude mouse model in the absence of detectable drug-induced toxicity during and after tumor regression. These findings indicate that 9NC may develop into a chemotherapeutic drug for the effective treatment of prostate cancer patients. Further, there was no apparent correlation of the steady-state level of the apoptosis-regulating proteins, Bcl-2, Bcl-XL, Bax and Ich-1, with tumorigenicity of the prostate cells xenografted in nude mice, aggressiveness of tumors grown in nude mice, and induction of apoptosis by 9NC. However, the TIAR protein was present at markedly high levels in all prostate carcinoma cell lines and this may correlate with their susceptibility to 9NC-induced apoptosis.

Animals↗
PubMed1995

Sensitivity of camptothecin-resistant human leukemia cells and tumors to anticancer drugs with diverse mechanisms of action.

Human leukemia U-937 cell clones resistant to 9-nitrocamptothecin (9NC) appear after exposure to increase 9NC-concentrations. Drug resistance is irreversible, regardless of whether the 9NC-resistant (U-937/CR150) cells grow in media with or without 9NC. U-937/CR150 cells are more sensitive than wild type U-937 (U-937/wt) cells to topoisomerase II-directed drugs, amsacrine, daunorubicin, and etoposide. The mitotic inhibitor, vincristine, induces hyperdiploidy in U-937/wt, but not in U-937/CR150 cells, whereas the antimetabolites, cytarabine and methotrexate, and the nitrosourea, carmustine, elicit similar responses in both U-937/wt and U-937/CR150 cells. U-937/CR150-generated tumors in nude mice are sensitive to etoposide. The clinical implications of increased sensitivity of 9NC-resistant tumors to some anticancer drugs are discussed.

Animals↗
PubMed1995

Evidence for a G2 checkpoint in p53-independent apoptosis induction by X-irradiation.

The p53 tumor suppressor gene is thought to be required for the induction of programmed cell death (apoptosis) initiated by DNA damage. We show here, however, that the human promyelocytic leukemia cell line HL-60, which is known to be deficient in p53 because of large deletions in the p53 gene, can be induced to undergo apoptosis following X-irradiation. We demonstrate that the decision to undergo apoptosis in this cell line appears to be made at a G2 checkpoint. In addition, we characterize an HL-60 variant, HCW-2, which is radioresistant. HCW-2 cells display DNA damage induction and repair capabilities identical to those of the parental HL-60 cell line. Thus, the difference between the two cell lines appears to be that X-irradiation induces apoptosis in HL-60, but not in HCW-2, cells. Paradoxically, HCW-2 cells display high levels of expression of bax, which enhances apoptosis, and no longer express bcl-2, which blocks apoptosis. HCW-2 cells' resistance to apoptosis may be due to the acquisition of expression of bcl-XL, a bcl-2-related inhibitor of apoptosis. In summary, apoptosis can be induced in X-irradiated HL-60 cells by a p53-independent mechanism at a G2 checkpoint, despite the presence of endogenous bcl-2. The resistance shown by HCW-2 cells suggests that bcl-XL can block this process.

Apoptosis↗
PubMed1994

Development of resistance to 9-nitro-camptothecin by human leukemia U-937 cells in vitro correlates with altered sensitivities to several anticancer drugs.

We have recently reported that exposure of human leukemia U-937 cells to progressively increasing concentrations of 9-nitro-camptothecin (9NC) resulted in cell sublines exhibiting various levels of resistance to 9NC. Here, we report responses of wild-type (U-937/wt) and 9NC-resistant (U-937/CR) cells to various anticancer drugs used extensively in cancer chemotherapy. U-937/CR cells were more sensitive than U-937/wt cells to several commonly used drugs of diverse origin including the topoisomerase II-directed drugs amsacrine, etoposide and daunorubicin; the vinca alkaloid vincristine; and the antimetabolite methotrexate. No responses were induced by carmustine in either cell type, whereas similar responses were induced by cytarabine. The sensitivity to the drugs was investigated by monitoring cell proliferation, by determining cell cycle perturbations assessed by flow cytometry analysis of DNA content and by microscopy of stained cells. The results in this report indicate that development of 9NC resistance by the U-937 cells is accompanied by increased sensitivities to other anticancer drugs in vitro and very likely in vivo.

Antineoplastic Agents↗
PubMed1993

Sexual aggression and love styles: an exploratory study.

The relationship between sexual aggression and theoretical love styles was studied. Based on self-reported sexual history, 63 college men were grouped as having either consensual sexual experience only (n = 33) or having verbally coercive sexual experience (n = 30). Analyses were conducted using six love style scales, likelihood to rape, likelihood to use sexual force, masculinity, and sociopathy to predict sexual coercive group membership. Logistic regression indicated that the Ludus love style, a manipulative, game-playing orientation towards intimate relationships, was the best predictor of sexual coercion among the six love styles. Additionally, logistic regression indicated that the Ludus love style was as effective in classifying men as coercive or noncoercive as other dispositions related to sexual aggression. These results suggest that the Ludus love style may serve as a unifying construct for dispositions related to sexual aggression. This study constitutes an initial attempt to link sexually coercive behaviors to a theoretical model of intimate relationships. Results are discussed in the context of a situational model of sexual coercion.

Adult↗
PubMed1983

Altered atrial responses to drugs after acute exposure to nitrogen dioxide and/or ethanol.

The responses of atria isolated from four groups of rats: (a) control (air/H2O) and test animals treated with (b) 5 PPM nitrogen dioxide NO2 for 72 hours, (NO2/H2O), (c) 10% ethanol (ET) in water for 13 days, (air/ET), or (d) combination of NO2 and ET (NO2/ET). Isolated atria were tested with norepinephrine and dose response curves determined. The chronotropic responses among groups were not different. However, there were significant differences when tested with pilocarpine and to lesser extent to increased calcium concentration in the bathing medium. Ethanol and/or NO2 attenuates parasympathetic activity possibly by altering receptor numbers or activity. The changes in calcium activity may result from altered calcium channel activity. This data indicates that acute exposure to NO2, ET and/or the interaction between these agents can alter cardiac activity.

Animals↗
PubMedDate not supplied

Development of human leukemia U-937 cell sublines resistant to doxorubicin: induction of differentiation and altered sensitivities to topoisomerase-directed drugs.

Cell sublines resistant to doxorubicin (DOX) were developed from the human leukemia cell line, U-937/WT, exposed to stepwise DOX increases. In contrast to U-937/WT cells, the DOX-resistant U-937/RD cells have longer doubling time; are more differentiated along the monocytic lineage as determined by the presence of morphological features and mRNA coding for the monocyte colony-stimulating factor-1 receptor; synthesize the apoptosis-associated Bax protein; are less sensitive to apoptosis-inducing topoisomerase II-directed drugs, apparently because of increased synthesis of P-glycoprotein; and are practically non-tumorigenic when xenografted in nude mice. However, U-937/WT and U-937/RD cells exhibit similar sensitivity to the apoptosis-inducing drug 9-nitrocamptothecin. These findings suggest that several mechanisms are involved in the development of DOX-resistance in U-937 cells, and further, 9-nitrocamptothecin can overcome resistance to DOX. These findings may have clinical implications.

ATP Binding Cassette Transporter, Subfamily B, Mem↗