96 results on '"Panasci, L. C."'
Search Results
2. Intrathecal trastuzumab and thiotepa for leptomeningeal spread of breast cancer
- Author
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Ferrario, C, Davidson, A, Bouganim, N, Aloyz, R, and Panasci, L C
- Published
- 2009
3. SarCNU (2-chloroethyl-3-sarcosinamide-1-nitrosourea): a novel analogue of chloroethylnitrosourea that is transported by the catecholamine uptake2 carrier, which mediates increased cytotoxicity
- Author
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Panasci, L. C., Marcantonio, Daniela, and Noë, Adrian J.
- Published
- 1996
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4. Ki 67 is a major, but not the sole determinant of Oncotype Dx recurrence score
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Sahebjam, S, primary, Aloyz, R, additional, Pilavdzic, D, additional, Brisson, M-L, additional, Ferrario, C, additional, Bouganim, N, additional, Cohen, V, additional, Miller, W H, additional, and Panasci, L C, additional
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- 2011
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5. The role of Ki-67 proliferation index vis-à-vis Oncotype DX.
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Sahebjam, S., primary, Aloyz, R., additional, Pilavdzic, D., additional, Brisson, M., additional, Ferrario, C., additional, Bouganim, N., additional, Cohen, V., additional, Miller, W. H., additional, and Panasci, L. C., additional
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- 2011
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6. Phase Ib study of sorafenib and vinorelbine as first-line treatment in patients with metastatic breast cancer.
- Author
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Ferrario, C., primary, Charamis, H., additional, Oyewole-Eletu, S., additional, Mihalcioiu, C. L., additional, Langleben, A., additional, Miller, W. H., additional, Aloyz, R., additional, and Panasci, L. C., additional
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- 2010
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7. An open-label, phase II study of weekly nab-paclitaxel as first-line therapy for patients (pts) with metastatic breast cancer (MBC): Safety update.
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Brezden, C. B., primary, Cantin, G., additional, Younus, J., additional, Panasci, L. C., additional, Klimo, P., additional, Laing, K. E., additional, Raymond, N., additional, Lam, W., additional, Trudeau, M. E., additional, and Robidoux, A., additional
- Published
- 2010
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8. Trastuzumab and vinorelbine (TV) in early stages of breast cancer
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Ferrario, C., primary, Wong, A., additional, Bouganim, N., additional, Gao, T., additional, Aloyz, R., additional, and Panasci, L. C., additional
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- 2009
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9. Inhibition of DNA repair in chronic lymphocytic leukemia: Therapeutic implications
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Amrein, L., primary, Aloyz, R., additional, and Panasci, L. C., additional
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- 2006
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10. Pegylated liposomal doxorubicin (PLD) with cyclophosphamide (C) as 1st-line chemotherapy for metastatic breast cancer (MBC) patients previously treated with adjuvant anthracyclines
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Vandenberg, T. A., primary, Trudeau, M., additional, Provencher, L., additional, Panasci, L. C., additional, Yelle, L., additional, Rayson, D., additional, Latreille, J., additional, Clemons, M., additional, Giroux, M., additional, and Pouliot, J., additional
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- 2006
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11. In Vitro Evidence for Homologous Recombinational Repair in Resistance to Melphalan
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Wang, Z.-M., primary, Chen, Z.-P., additional, Xu, Z.-Y., additional, Christodoulopoulos, G., additional, Bello, V., additional, Mohr, G., additional, Aloyz, R., additional, and Panasci, L. C., additional
- Published
- 2001
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12. Re: Five Versus More Than Five Years of Tamoxifen Therapy for Breast Cancer Patients With Negative Lymph Nodes and Estrogen Receptor-Positive Tumors
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Panasci, L. C., primary and Melnychuk, D., additional
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- 1997
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13. SarCNU (2-chloroethyl-3-sarcosinamide-1-nitrosourea): a novel analogue of chloroethylnitrosourea that is transported by the catecholamine uptake 2 carrier, which mediates increased cytotoxicity
- Author
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Panasci, L. C., primary, Marcantonio, Daniela, additional, and Noë, Adrian J., additional
- Published
- 1996
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- View/download PDF
14. Lack of evidence for a high-affinity sarcosinamide carrier or a catecholamine carrier in Calu-1 lung-cancer cells, HT-29 colon-cancer cells, and DHF fibroblasts.
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Malapetsa, Areti, Bramson, Jonathan, Noë, Adrian, Panasci, Lawrence, Malapetsa, A, Bramson, J L, Noë, A J, and Panasci, L C
- Subjects
ADRENALINE ,BIOLOGICAL transport ,COLON tumors ,COMPARATIVE studies ,DRUG delivery systems ,FIBROBLASTS ,GLYCINE ,LUNG tumors ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,RESEARCH funding ,EVALUATION research ,CANCER cell culture - Abstract
We have previously demonstrated that uptake of the amino acid amide sarcosinamide by the glioma cell line SK-MG-1 occurs via the catecholamine carrier that accommodates epinephrine (Km = 0.284 mM; Vmax = 0.154 nmol/10(6) cells/min). Sarcosinamide chloroethylnitrosourea (SarCNU), a new anticancer agent that exerts increased in vitro antitumor activity against gliomas as compared with BCNU (bis-chloroethylnitrosourea), the standard agent of choice, competitively inhibits sarcosinamide uptake by SK-MG-1 cells [inhibition constant (Ki) = 3.26 mM]. Using radiolabeled N-[3H]-sarcosinamide, we determined the transport of sarcosinamide in HT-29 colon-cancer cells, in Calu-1 lung-cancer cells, and in normal foreskin DHF fibroblasts. Sarcosinamide transport was linear for up to 1 min at 22 degrees C. In HT-29 cells and DHF fibroblasts, the uptake of sarcosinamide followed Michaelis-Menten kinetics of carrier-mediated transport. In HT-29 cells the Michaelis constant (Km) was 2.76 +/- 0.1 mM and the maximal velocity (Vmax) was 2.03 +/- 0.1 nmol/10(6) cells/min, whereas in DHF fibroblasts the respective values were 6.58 +/- 3.90 mM and 12.08 +/- 8.20 nmol/10(6) cells/min. In these two cell lines, neither epinephrine nor leucine significantly reduced sarcosinamide transport. In Calu-1 cells there was no evidence of carrier-mediated transport of either sarcosinamide or epinephrine. These nonglial cell lines lack a high-affinity catecholamine carrier. The increased cytotoxicity of SarCNU in gliomas may correlate with the presence of a high-affinity catecholamine carrier. [ABSTRACT FROM AUTHOR]
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- 1992
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15. Statin expression in the untreated and SarCNU-exposed human glioma cell line, SK-MG-1.
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Schipper, Hyman, Skalski, Violetta, Panasci, Lawrence, Wang, Eugenia, Schipper, H M, Skalski, V, Panasci, L C, and Wang, E
- Abstract
Cytokinetic analyses of gliomas and other neoplasms rely exclusively on the use of proliferation-dependent markers such as [3H]-thymidine and BuDR incorporation and the detection of growth-dependent proteins such as proliferating cell nuclear antigen (PCNA) and Ki-67. In normal tissues, the monoclonal antibody S-44 recognizes statin, a nuclear protein expressed only in nonproliferating cells. In the present study, indirect immunofluorescence microscopy using S-44 identified nuclear statin in 5.9% of a population of untreated human SK-MG-1 glioma cells in vitro. Incremental doses of the alkylating agent sarcosinamide chloroethylnitrosourea (SarCNU) induced a linear increase in the fraction of statin-positive SK-MG-1 cells. Labeling of nuclear statin with the monoclonal antibody S-44 may be a potentially useful marker of the cytotoxic effects of anticancer drugs in gliomas and other neoplastic tissues. [ABSTRACT FROM AUTHOR]
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- 1990
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16. In vitro comparative studies of the myelotoxicity and antitumor activity of 6-[bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose versus melphalan utilizing the CFU-C and HTSCA assays.
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Lazarus, Philip, Dufour, Maurice, Isabel, Guy, Panasci, Lawrence, Lazarus, P, Dufour, M, Isabel, G, and Panasci, L C
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ANALYSIS of variance ,BIOCHEMISTRY ,BONE marrow ,COMPARATIVE studies ,PHENOMENOLOGY ,RESEARCH methodology ,MEDICAL cooperation ,MELANOMA ,NITROGEN mustards ,OVARIAN tumors ,RESEARCH ,RESEARCH funding ,EVALUATION research ,IN vitro studies ,COLONY-forming units assay ,MELPHALAN ,THERAPEUTICS - Abstract
6-[Bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose (C-6) is a new glucose-containing nitrogen mustard that has significant activity for murine P388 leukemia with relative sparing of bone marrow in mice. The in vitro myelotoxicity of C-6 compared with that of melphalan, a clinically active, myelosuppressive nitrogen mustard, was determined in the CFU-C assay in human bone marrow samples obtained from normal volunteers. There was no significant difference between the myelosuppressive actions of C-6 and melphalan at any of the concentrations used except for 4.0 microM, at which C-6 was significantly (P less than 0.05) more toxic than melphalan. Both agents decreased the number of bone marrow cell colonies to approximately 12% of control at 6.6 microM (1 h incubation), which is a good approximation of melphalan's CxT (concentration by time) in man. We used the human tumor stem cell assay (HTSCA) to investigate in vitro antitumor activity. We obtained two specimens of malignant melanoma and two of malignant ovarian carcinoma from patients not previously treated with chemotherapy. The antitumor activity of melphalan was either similar to or greater than that of C-6 at all concentrations utilized against any of the four tumor specimens, except at 1.3 microM for tumor I. In particular, there was no significant difference in the antitumor activities of the two agents at 6.6 microM. These results suggest that C-6 will not be less myelosuppressive than melphalan at doses that produce equivalent antitumor activity in man. In addition, C-6 did not demonstrate increased myelotoxicity for normal human bone marrow cells incubated in glucose-deficient medium as against medium containing 300 mg% glucose at any of the concentrations used. This suggests that C-6 is not transported into normal human bone marrow cells via the glucose transport system, despite the presence of a glucose moiety within the molecule. [ABSTRACT FROM AUTHOR]
- Published
- 1986
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17. Effects of amino acids on the transport and cytotoxicity of melphalan by human bone marrow cells and human tumor cells.
- Author
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Dufour, Maurice, Panasci, Lawrence, Germain, Judith, Boulet, Louise, Dufour, M, Panasci, L C, St Germain, J, and Boulet, L
- Abstract
In human tumor cells freshly obtained from patients with breast cancer, ovarian cancer, or adenocarcinoma of unknown etiology and in normal human bone marrow cells, the cell-to-medium ratio (intracellular/extracellular concentration) in vitro of 5.42 microM melphalan rose rapidly to levels of 6-17 after 35 min at 37 degrees C in Dulbecco's phosphate-buffered saline containing bovine serum albumin and glucose. Only patient C (breast cancer) had received chemotherapy. In all cells studied, L amino acids (1 mM) such as leucine, glutamine, tyrosine, and methionine reduced the cell-to-medium ratio of melphalan at 3 and 35 min. There was a good correlation between the reduction of melphalan transport at 35 min in the heterogeneous nucleated bone marrow cell population by amino acids and their effect on melphalan cytotoxicity in the CFU-C system. Aminoisobutyric acid (A1B), a specific substrate of the A system of amino acid transport, at a concentration between 1 and 50 mM had no significant effect on melphalan uptake at 3 min in any of the human cells studied except those of patient C. At 35 min A1B (10 or 50 mM) significantly reduced the intracellular melphalan concentration in normal bone marrow cells and tumor cells from patients B and C. At 2 mM, 2-aminobicyclo-(2, 2,1)-heptane-2-carboxylic acid (BCH), a specific substrate of the L system of amino acid transport, reduced the cell-to-medium ratio to 70% of control at 3 and 35 min in human bone marrow cells. In tumor cells from patients A, B, D, and F, 2 mM BCH had no significant effect on melphalan uptake at 3 min; it slightly decreased uptake in tumor cells from patient C. At 35 min, 2 mM BCH significantly reduced melphalan transport in tumor cells from patients C and F only. The lack of a BCH-suppressible component to melphalan uptake into human tumor cells freshly obtained from previously untreated patients contrasts with the presence of this component in murine L1210 leukemia cells, murine P388 leukemia cells, and human tumor cell lines. This suggests that minor differences in melphalan transport may exist amongst species and also between human tumor cells which are freshly obtained and cell lines maintained in culture. [ABSTRACT FROM AUTHOR]
- Published
- 1985
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18. Utilization of the HTSCA and CFU-C assay to identify two new 2-chloroethylnitrosourea congeners of amino acid amides with increased in vitro activity against human glioma compared with BCNU.
- Author
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Panasci, Lawrence, Dufour, Maurice, Chevalier, Lina, Isabel, Guy, Lazarus, Philip, McQuillan, Angela, Arbit, Ehud, Brem, Steven, Feindel, William, Panasci, L C, Dufour, M, Chevalier, L, Isabel, G, Lazarus, P, McQuillan, A, Arbit, E, Brem, S, and Feindel, W
- Abstract
AspCNU and SarCNU are two amino acid amide congeners (L-asparaginamide and sarcosinamide congeners) of chloroethylnitrosoureas. The in vitro myelotoxicity of these agents compared with BCNU at 1-8 micrograms/ml was determined in bone marrow cells from normal volunteers in the CFU-C assay. AspCNU and SarCNU were significantly (P less than 0.05) less myelotoxic than BCNU at equivalent microgram concentrations. SarCNU or AspCNU at 3 micrograms/ml demonstrate equivalent in vitro myelotoxicity to BCNU 1 microgram/ml. We used the human tumor stem cell assay (HTSCA) to investigate in vitro antitumor activity. We obtained four specimens of malignant glioma and one specimen of meningioma from patients not previously treated with chemotherapy. AspCNU and SarCNU were significantly (P less than 0.05) more active than BCNU at 1-3 micrograms/ml concentrations in the HTSCA in all four malignant glioma specimens. In the one meningioma specimen, BCNU was significantly (P less than 0.05) more active than either AspCNU or SarCNU at all concentrations studied. These results suggest that AspCNU or SarCNU at doses that should produce less myelotoxicity than BCNU may be more active than BCNU against gliomas. [ABSTRACT FROM AUTHOR]
- Published
- 1985
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19. Effect of administration of sodium cyanate and melphalan on the lifespan of P388 tumor-bearing CD2F1 mice.
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Dufour, Maurice, Germain, Judith, Skalski, Violetta, Dorato, Andrea, Lazarus, Philip, Panasci, Lawrence, Dufour, M, St Germain, J, Skalski, V, Dorato, A, Lazarus, P, and Panasci, L C
- Abstract
Sodium cyanate (NaOCN) at a dose of 250 mg/kg was shown to decrease protein synthesis in P388 leukemia tumor cells to approximately 52% of control values at 2 h and 32% at 5 h after NaOCN administration, without a corresponding decrease in various normal tissues of the tumor-bearing CD2Fl mice. CD2Fl mice that had received P388 tumor cells IP 1 day prior to drug administration underwent various schedules of treatment with NaOCN and melphalan (MLN). NaOCN (200 mg/kg or 250 mg/kg) administered IP has no significant antitumor activity (increased mean lifespan [ILS] less than 20%). The simultaneous IP administration of NaOCN (250 mg/kg) plus MLN (15 mg/kg) resulted in a significantly greater antitumor activity (approximately 265% of control, with 21 of 30 animals being long-term survivors) than MLN (15 mg/kg) alone (approximately 156% of control, with 11 of 30 animals being long-term survivors). This synergism was not observed when MLN was administered 4 h after NaOCN administration. The synergistic activity of MLN with NaOCN does not appear to be secondary to alterations in the absorption from the peritoneal cavity into the systemic circulation as determined by 3H2O. NaOCN does not increase the intracellular concentration of [chloroethyl-14C]MLN into P388 cells. The mechanism of the synergistic antitumor activity of simultaneous IP administration of NaOCN and MLN is unknown. [ABSTRACT FROM AUTHOR]
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- 1984
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20. Biological activity, binding, and metabolic fate of Ac-[Nle4, D-Phe7]α-MSH4-11NH2 with the F1 variant of B16 melanoma cells.
- Author
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Panasci, L. C., McQuillan, A., and Kaufman, M.
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- 1987
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21. Mechanisms of resistance to (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU) in sensitive and resistant human glioma cells.
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Skalski, V, Yarosh, D B, Batist, G, Gros, P, Feindel, W, Kopriva, D, and Panasci, L C
- Abstract
Resistance to (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU), an experimental antitumor compound, was investigated in the sensitive SK-MG-1 cells and the 20-fold more resistant SKI-1 human glioma cells [which are 3-fold more resistant to 1,3,bis(2-chloroethyl)-1-nitrosourea (BCNU)]. The transport of SarCNU was examined by utilizing tritiated sarcosinamide. Sarcosinamide uptake into SK-MG-1 cells is via the catecholamine carrier that accommodates epinephrine. Dixon plot analysis of SarCNU inhibition of sarcosinamide uptake reveals that SarCNU is also accommodated by this carrier. The uptake of 0.5 mM [3H]sarcosinamide was temperature dependent, with similar levels of intracellular sarcosinamide accumulating at steady state in both cell lines. The uptake of sarcosinamide in SKI-1 cells obeyed Michaelis-Menten kinetics over a 200-fold range of concentrations with a Km of 1.52 +/- 0.151 mM and Vmax of 0.659 +/- 0.066 nmol/10(6) cells/min. This represents a more than 5-fold decrease in the uptake affinity and a more than 4-fold increase in the transport capacity compared with SK-MG-1 cells (Km = 0.282 +/- 0.041 mM; Vmax = 0.154 +/- 0.024 nmol/10(6) cells/min). The initial rate of sarcosinamide uptake is similar in both cell lines. Dixon plot analysis confirmed that SarCNU is a competitive inhibitor of sarcosinamide transport in SKI-1 cells with a Ki of 17.5 mM, which is more than 5-fold greater than the Ki obtained in SK-MG-1 cells. The steady state accumulation of SarCNU is significantly reduced by 47% in SKI-1 cells compared with the SK-MG-1 cells (cell to medium ratios of 0.65 +/- 0.11 and 1.22 +/- 0.08, respectively) (p less than 0.005). The accumulation of BCNU was comparable in the two cell lines. Since the Vmax of sarcosinamide (SarCNU) uptake is increased in the SKI-1 cells, the decrease in intracellular SarCNU is not related to decreased drug influx via the catecholamine carrier in SKI-1 cells. The efflux of tritiated sarcosinamide was temperature dependent and similar in both cell lines, with 54 and 58% of sarcosinamide being freely exchangeable in SKI-1 and SK-MG-1 cells, respectively. SarCNU efflux may or may not be altered. Since the expression of mdr is higher in the sensitive cells, it is unlikely that increased efflux of SarCNU mediated by the P-glycoprotein is responsible for drug resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1990
22. Characterization of the Catecholamine Extraneuronal Uptake~2 Carrier in Human Glioma Cell Lines SK-MG-1 and SKI-1 in Relation to (2-Chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU) Selective Cytotoxicity
- Author
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Noe, A. J., Marcantonio, D., Barton, J., Malapetsa, A., and Panasci, L. C.
- Published
- 1996
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- View/download PDF
23. Transport of (2-chloroethyl)-3-sarcosinamide-1-nitrosourea in the human glioma cell line SK-MG-1 is mediated by an epinephrine-sensitive carrier system.
- Author
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Noë, A J, Malapetsa, A, and Panasci, L C
- Abstract
The transport of (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU), an experimental anticancer compound, was investigated in the human glioma cell line SK-MG-1. The transport of [3H]SarCNU was examined in suspension. The uptake of [3H] SarCNU was found to be temperature dependent, with influx being linear to 4 sec at 37 degrees. Equilibrium was reached after 1 min at 22 degrees and 37 degrees, with accumulation slightly above unity. SarCNU was not significantly metabolized in the cells after a 60-min incubation at 37 degrees, as shown by thin layer chromatography. At 37 degrees, uptake of [3H]SarCNU was found to be saturable, sodium independent, and energy independent. Previous work demonstrated that SarCNU was able to inhibit the uptake of sarcosinamide, which is transported by the catecholamine uptake 2 system. This catecholamine system mediates the physiological transport of epinephrine. Epinephrine was able to significantly inhibit the uptake of [3H]SarCNU, at a concentration of 50 microM, by 40%. Additionally, several amino acids were unable to inhibit the uptake of SarCNU. The initial rate of SarCNU influx is mediated by both facilitated and nonfacilitated diffusion. The nonfacilitated diffusion rate could be estimated from the linear concentration dependence of the residual influx rate for SarCNU, which was not inhibited by the presence of excess co-permeant (epinephrine). Dixon plot analysis, corrected for nonfacilitated diffusion of SarCNU, revealed that epinephrine inhibited the uptake of SarCNU competitively, with a Ki of 163 +/- 15 microM, a value similar to the Km value for epinephrine influx in SK-MG-1 cells. Additionally, after appropriate corrections for nonfacilitated diffusion in the influx rates observed for SarCNU, it was revealed that SarCNU influx obeyed Michaelis-Menten kinetics over a 200-fold range of concentrations, with a Km of 2.39 +/- 0.37 mM and a Vmax of 236 +/- 53 pmol/microliters of intracellular water/sec. Metabolic poisons (2,4-dinitrophenol, iodoacetate, NaCN, NaF, or ouabain) were unable to inhibit the influx of SarCNU, suggesting that the carrier-mediated uptake of SarCNU is energy independent and mediated by facilitated diffusion. These findings indicate that SarCNU uptake in SK-MG-1 cells is mediated both by nonfacilitated diffusion and by facilitated diffusion via the catecholamine uptake 2 carrier system. SarCNU is the first chloroethylnitrosourea that has been demonstrated to have carrier-mediated uptake. Moreover, this carrier-mediated uptake may play a role in the increased cytotoxicity of SarCNU against gliomas, compared with that of 1,3-bis(2,-chloroethyl)-1-nitrosourea, which enters cells primarily by passive diffusion.
- Published
- 1993
24. Evidence for increased αMSH receptor binding in the F1 variant of B16 melanoma cells grown in dialyzed fetal calf serum.
- Author
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McQuillan, A., Hutchinson, M., and Panasci, L. C.
- Published
- 1989
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25. Comparison of the transport of chlorozotocin and CCNU in L1210 leukemia and murine bone marrow cells in vitro.
- Author
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Lazarus, Philip, Germina, Judith, Dufour, Maurice, Palmer, Greg, Wallace, Deborah, Panasci, Lawrence, Lazarus, P, Germina, J S, Dufour, M, Palmer, G, Wallace, D, and Panasci, L C
- Subjects
ANIMAL experimentation ,ANTINEOPLASTIC agents ,BIOLOGICAL transport ,BONE marrow ,COMPARATIVE studies ,LEUKEMIA ,RESEARCH methodology ,MEDICAL cooperation ,MICE ,RESEARCH ,RESEARCH funding ,EVALUATION research ,IN vitro studies - Abstract
The uptake of radiolabeled CLZ and CCNU by L1210 leukemia and murine bone marrow cells was investigated to determine whether the preferential ratio of alkylation of L1210 DNA to murine bone marrow DNA of 1.3 by 0.1 mM CLZ, as against a ratio of 0.6 by equimolar CCNU, is secondary to differences in uptake. The concentration of intact CLZ was determined in the medium and the intracellular water space. The cell: medium ratio (intracellular concentration/medium concentration) of CLZ in bone marrow cells was greater than that seen for L1210 cells. However, the intracellular CLZ concentration generally remained constant in both cell types at 37 degrees C, between 7.0 and 10.0 pmole/microliters. The L1210: murine bone marrow cell ratio of intracellular CLZ concentrations was approximately 1.0 from 10 to 60 min. The intracellular CCNU concentration during the uptake of 0.1 mM (chloroethyl-U-14C) CCNU at 37 degrees C was constant at 85 pmol/microliters from 10 to 60 min in L1210 cells, but slowly decreased from 66 pmole/microliters at 20 min to 43 pmole/microliters at 60 min in bone marrow cells. The L1210: murine bone marrow cell ratio of intracellular CCNU concentrations ranged from 1.45 to 1.98 from 20 to 60 min. Thus, it appears that the preferential ratio of alkylation of L1210 DNA to murine bone marrow DNA by CLZ compared with equimolar CCNU cannot be explained by differences in uptake of the two agents by the two cell types. The uptake of 0.1 mM CLZ at 37 degrees C by L1210 cells in McCoy's 5A medium containing 300 mg% glucose was not affected by the addition of 5 mM cold drug, nor was it affected by the absence of glucose in the medium, with or without cold drug. This suggests that CLZ uptake into L1210 cells is via passive diffusion and that CLZ does not enter these cells via the glucose transport mechanism. [ABSTRACT FROM AUTHOR]
- Published
- 1983
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26. Biological activity, binding, and metabolic fate of Ac-[Nle4, D-Phe7]?-MSH4-11NH2 with the F1 variant of B16 melanoma cells
- Author
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Panasci, L. C., primary, McQuillan, A., additional, and Kaufman, M., additional
- Published
- 1987
- Full Text
- View/download PDF
27. Evidence for increased ?MSH receptor binding in the F1 variant of B16 melanoma cells grown in dialyzed fetal calf serum
- Author
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McQuillan, A., primary, Hutchinson, M., additional, and Panasci, L. C., additional
- Published
- 1989
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28. Poorly differentiated carcinoma or extragonadal germ cell cancer.
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Gonzalez Vela, Jose Luis, Shenouda, George, Panasci, Lawrence Carl, Gonzalez Vela, J L, Shenouda, G, and Panasci, L C
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LETTERS to the editor ,CANCER ,CANCER diagnosis ,GERM cell tumors ,IMMUNOENZYME technique - Abstract
A letter to the editor is presented in response to the article "Advanced poorly differentiated carcinoma of unknown primary site: recognition of a treatable syndrome," by FA Greco and colleagues, in a 1986 issue.
- Published
- 1987
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29. DNA repair enzyme expression in chronic lymphocytic leukemia vis-a-vis nitrogen mustard drug resistance
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Bramson, J., McQuillan, A., and Panasci, L. C.
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- 1995
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30. Trastuzumab and vinorelbine in early stages of HER2-positive breast cancer.
- Author
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Ferrario C, Wong A, Gao T, Bouganim N, Aloyz R, and Panasci LC
- Subjects
- Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms blood, Breast Neoplasms enzymology, Breast Neoplasms pathology, Chemotherapy, Adjuvant, Disease-Free Survival, Drug Tolerance, Female, Humans, Middle Aged, Neoplasm Staging, Neutropenia chemically induced, Retrospective Studies, Trastuzumab, Vinblastine administration & dosage, Vinblastine adverse effects, Vinblastine analogs & derivatives, Vinorelbine, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Breast Neoplasms drug therapy, Receptor, ErbB-2 biosynthesis
- Abstract
The combination of vinorelbine and trastuzumab (VH) is highly active and well tolerated in patients with metastatic HER2+ breast cancer. We assessed the efficacy and tolerability of VH as an alternative adjuvant treatment for patients with localized breast cancer refusing or ineligible for standard adjuvant trastuzumab-based chemotherapy. Twenty-eight patients with stage I-III breast cancer were treated only with VH as preoperative or postoperative chemotherapy. Fourteen patients received VH as adjuvant treatment for pT1a-b pN0 or eR+ pT1c pN0 cancers. VH was well tolerated, the only grade 3-4 toxicity being neutropenia with 2 cases of febrile neutropenia. At a median follow-up of 39 months, no breast cancer relapses were documented; moreover, overall and disease-free survival was 96.4%. In summary, our results indicate that VH is effective and well tolerated. VH should be prospectively tested as adjuvant treatment for pN0 pT1a-b breast cancer patients for which no standard treatment is well defined.
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- 2011
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31. In vitro evidence for homologous recombinational repair in resistance to melphalan.
- Author
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Wang ZM, Chen ZP, Xu ZY, Christodoulopoulos G, Bello V, Mohr G, Aloyz R, and Panasci LC
- Subjects
- Blotting, Western, DNA, Neoplasm metabolism, DNA-Activated Protein Kinase, DNA-Binding Proteins genetics, DNA-Binding Proteins physiology, Fluorescent Antibody Technique, Indirect, Humans, Ku Autoantigen, Microscopy, Confocal, Neoplasm Proteins genetics, Nuclear Proteins genetics, Nuclear Proteins physiology, Protein Serine-Threonine Kinases analysis, Rad51 Recombinase, Sequence Homology, Nucleic Acid, Tumor Cells, Cultured drug effects, Antigens, Nuclear, Antineoplastic Agents, Alkylating pharmacology, Cross-Linking Reagents pharmacology, DNA Helicases, DNA Repair, DNA, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Melphalan pharmacology, Neoplasm Proteins physiology, Recombination, Genetic
- Abstract
Background: The generation of DNA interstrand cross-links is thought to be important in the cytotoxicity of nitrogen mustard alkylating agents, such as melphalan, which have antitumor activity. Cell lines with mutations in recombinational repair pathways are hypersensitive to nitrogen mustards. Thus, resistance to melphalan may require accelerated DNA repair by either recombinational repair mechanisms involving Rad51-related proteins (including x-ray repair cross-complementing proteins Xrcc2, Xrcc3, and Rad52) or by nonhomologous endjoining involving DNA-dependent protein kinase (DNA-PK) and Ku proteins. We investigated the role of DNA repair in melphalan resistance in epithelial tumor cell lines., Methods: Melphalan cytotoxicity was determined in 14 epithelial tumor cell lines by use of the sulforhodamine assay. Homologous recombinational repair involving Rad51-related proteins was investigated by determining the levels of Rad51, Rad52, and Xrcc3 proteins and the density of nuclear melphalan-induced Rad51 foci, which represent sites of homologous recombinational repair. Nonhomologous endjoining was investigated by determining the levels of Ku70 and Ku86 proteins and DNA-PK activity. Linear regression analysis was used to analyze correlations between the various protein levels, DNA-PK activity, or Rad51 foci formation and melphalan cytotoxicity. All statistical tests were two-sided., Results: Melphalan resistance was correlated with Xrcc3 levels (r =.587; P =.027) and the density of melphalan-induced Rad51 foci (r =.848; P =.008). We found no correlation between melphalan resistance and Rad51, Rad52, or Ku protein levels or DNA-PK activity., Conclusion: Correlations of melphalan resistance in epithelial tumor cell lines with Xrcc3 protein levels and melphalan-induced Rad51 foci density suggest that homologous recombinational repair is involved in resistance to this nitrogen mustard.
- Published
- 2001
- Full Text
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32. Aromatase inhibitors: treatment of advanced breast cancer.
- Author
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Panasci LC
- Subjects
- Antineoplastic Agents therapeutic use, Bone Density drug effects, Female, Humans, Letrozole, Middle Aged, Nitriles therapeutic use, Randomized Controlled Trials as Topic, Triazoles therapeutic use, Antineoplastic Agents adverse effects, Aromatase Inhibitors, Breast Neoplasms drug therapy, Nitriles adverse effects, Osteoporosis, Postmenopausal chemically induced, Triazoles adverse effects
- Published
- 2001
- Full Text
- View/download PDF
33. Is anastrozole superior to tamoxifen as first-line therapy for advanced breast cancer?
- Author
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Panasci LC
- Subjects
- Anastrozole, Female, Humans, Middle Aged, Postmenopause, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Nitriles therapeutic use, Tamoxifen therapeutic use, Triazoles therapeutic use
- Published
- 2001
34. Both extraneuronal monoamine transporter and O(6)-methylguanine-DNA methyltransferase expression influence the antitumor efficacy of 2-chloroethyl-3-sarcosinamide- 1-nitrosourea in human tumor xenografts.
- Author
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Chen ZP, Wang ZM, Carter CA, Alley MC, Mohr G, and Panasci LC
- Subjects
- Animals, Carmustine analogs & derivatives, Carrier Proteins genetics, Disease Models, Animal, Gene Expression, HT29 Cells, Humans, Mice, Mice, Nude, O(6)-Methylguanine-DNA Methyltransferase genetics, Treatment Outcome, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Antineoplastic Agents therapeutic use, Carmustine therapeutic use, Carrier Proteins metabolism, O(6)-Methylguanine-DNA Methyltransferase metabolism, Organic Cation Transport Proteins
- Abstract
We previously have found that 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) is a selective cytotoxin that enters cells via the extraneuronal transporter for monoamine transmitters (EMT). Both in vitro and in vivo studies demonstrated that SarCNU was more effective than BCNU against human gliomas. To clarify whether EMT expression correlates with antitumor efficacy of SarCNU, we determined human EMT (EMTh) and O(6)-methylguanine-DNA methyltransferase (MGMT) expression in nine human xenograft models using semiquantitative reverse-transcription polymerase chain reaction. These results were compared with the antitumor effects of SarCNU and the standard chloroethylnitrosourea antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). There was no significant correlation between EMTh expression and antitumor efficacy of SarCNU or BCNU. Also, there was no significant correlation between MGMT expression and SarCNU efficacy. However, a significant correlation was found between MGMT expression and BCNU antitumor efficacy. Interestingly, multiple regression analysis demonstrated a significant correlation between SarCNU efficacy and EMTh plus MGMT expression, whereas there was no correlation between BCNU efficacy and MGMT plus EMTh expression. Thus, the absence of a linear correlation between SarCNU efficacy and EMTh expression appears to be due, at least in part, to the presence of DNA repair, specifically, MGMT, in these xenograft models. These studies suggest that MGMT expression alone correlates with BCNU activity, whereas both EMTh and MGMT expression are important determinants of SarCNU activity against human tumor xenograft models. SarCNU is in clinical trials and these results may have important clinical implications.
- Published
- 2001
35. [Expression of extraneuronal monoamine transporter gene and DNA repair gene vis-à-vis with antitumor efficacy of SarCNU in human tumor xenografts].
- Author
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Chen Z, Panasci LC, and Carter CA
- Subjects
- Animals, DNA Repair genetics, DNA-Binding Proteins genetics, Gene Expression Regulation, Neoplastic drug effects, HT29 Cells, Humans, Mice, Mice, Nude, Neoplasm Transplantation, Neoplasms, Experimental genetics, Neoplasms, Experimental pathology, Proteins genetics, RNA, Neoplasm genetics, RNA, Neoplasm metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Xeroderma Pigmentosum Group D Protein, Antineoplastic Agents therapeutic use, Carmustine analogs & derivatives, Carmustine therapeutic use, Carrier Proteins genetics, DNA Helicases, Neoplasms, Experimental drug therapy, O(6)-Methylguanine-DNA Methyltransferase genetics, Organic Cation Transport Proteins, Transcription Factors
- Abstract
Objective: To clarify if there are any correlations between extraneuronal monoamine transmitters (EMT), DNA repair gene expressions and SarCNU antitumor efficacy., Methods: EMT, DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) and excision repair cross-complementing rodent repair deficiency gene (ERCC1-6) expressions in 9 human xenograft tumor models were determined by RT-PCR. The results were compared with the antitumor effects of SarCNU on these tumor xenografts., Results: Multiple regression analysis revealed significant correlations of SarCNU antitumor activity with different combinations of gene expression. The most significant correlation was observed with all of the 4 genes expressed., Conclusion: The results suggest that expression of both EMT and DNA repair genes, specifically, MGMT, ERCC2 and ERCC4, are important determinants of SarCNU activity against human tumors. While DNA repair decreases SarCNU's activity by repairing damaged DNA, EMT appears to enhance its antitumor efficacy.
- Published
- 2001
36. [Anti-tumor efficacy of 2-chloroethyl-3-sarcosinamide-1-nitrosourea in a human lung cancer xenograft model with DNA repair gene expressions].
- Author
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Chen Z, Panasci LC, Carter CA, and Alley MC
- Abstract
Background: To clarify whether 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) has an anti-tumor effect in DNA repair gene expressing tumors., Methods: Human non-small cell lung cancer cell line,NCI-H522,was implanted into 25 athymic mice and 6 were treated with SarCNU 120mg/kg once a day for 5 times intraperitoneally (ip).The left ones were given normal saline.The extraneuronal monoamine transporter (EMT) expression,DNA repair gene O⁶-methylguanine-DNA methyltransferase (MGMT) and excision repair cross-complementing rodent repair deficiency gene (ERCC1-6) expressions were detected in the tumor specimens by using reverse-transcription polymerase chain reaction (RT-PCR).Comparison of tumor size change between two groups was illustrated with T/C%., Results: All the tumors were reduced in size through the treatment of SarCNU with the optimal T/C% of 23 at day 28.The tumor growth delay was 55 days,but no tumor free animals were observed.Positive EMT and DNA repair gene expression were observed in all tumor samples., Conclusions: The results suggest that anti-tumor effect of SarCNU in EMT positive tumor is satisfactory even though the tumor exhibits DNA repair gene expression,specifically MGMT and ERCC1-6.
- Published
- 2000
- Full Text
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37. Extraneuronal monoamine transporter expression and DNA repair vis-à-vis 2-chloroethyl-3-sarcosinamide-1-nitrosourea cytotoxicity in human tumor cell lines.
- Author
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Chen ZP, Remack J, Brent TP, Mohr G, and Panasci LC
- Subjects
- Blotting, Western, Carmustine toxicity, Carrier Proteins genetics, Drug Resistance, Neoplasm, Humans, O(6)-Methylguanine-DNA Methyltransferase biosynthesis, O(6)-Methylguanine-DNA Methyltransferase genetics, O(6)-Methylguanine-DNA Methyltransferase metabolism, Protein Biosynthesis, Proteins genetics, Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Xeroderma Pigmentosum Group D Protein, Antineoplastic Agents toxicity, Carmustine analogs & derivatives, Carrier Proteins biosynthesis, DNA Helicases, DNA Repair genetics, DNA-Binding Proteins, Organic Cation Transport Proteins, Transcription Factors, Tumor Cells, Cultured drug effects
- Abstract
We previously found that 2-chloroethyl-3-sarcosin-amide-1-nitrosourea (SarCNU), a new chloroethylnitrosourea analogue presently in phase I clinical trials, is a selective cytotoxin that enters cells via the extraneuronal transporter for monoamine transmitters (EMT). In this study, we assessed whether EMT expression correlates with SarCNU cytotoxicity by determining EMT expression in 23 human tumor cell lines with reverse-transcription PCR. Western blot analysis was used to measure protein levels of the DNA repair genes, O6-methylguanine-DNA methyltransferase (MGMT), and excision repair cross-complementing rodent repair deficiency gene 2 (ERCC2). SarCNU cytotoxicity was determined by the sulforhodamine B colorimetric anti-cancer-drug screening assay and correlated with gene expression. Almost all of the cell lines screened were positive for EMT expression. However, seven cell lines (MGR-1, MGR-2, T98-G, SKI-1, SKNSH, 297, and GBM) expressed low levels of EMT. Although there was no linear correlation between SarCNU cytotoxicity and EMT expression, SarCNU cytotoxicity significantly correlated with ERCC2 protein levels, and MGMT-rich (Mer+) cell lines (MGMT protein level >0.1) were more resistant to SarCNU than MGMT-poor (Mer-) cell lines (MGMT protein level <0.1). Moreover, multiple regression analysis indicated that the best correlation with SarCNU cytotoxicity was attainable with EMT plus MGMT and ERCC2 expression. This study suggests that in human tumor cell lines both EMT and DNA repair factors, specifically, MGMT and ERCC2, are important determinants of SarCNU activity. Because EMT is expressed in a wide variety of human tumors, SarCNU should be a more widely effective alternative chemotherapeutic agent.
- Published
- 1999
38. Chlorambucil induction of HsRad51 in B-cell chronic lymphocytic leukemia.
- Author
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Christodoulopoulos G, Malapetsa A, Schipper H, Golub E, Radding C, and Panasci LC
- Subjects
- B-Lymphocytes drug effects, B-Lymphocytes metabolism, Cells, Cultured, DNA Repair drug effects, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Fluorescent Antibody Technique, Gene Expression Regulation, Neoplastic drug effects, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Microscopy, Confocal, Rad51 Recombinase, Antineoplastic Agents, Alkylating pharmacology, Chlorambucil pharmacology, DNA-Binding Proteins biosynthesis, Leukemia, Lymphocytic, Chronic, B-Cell metabolism
- Abstract
Our previous studies with B-cell chronic lymphocytic leukemia (B-CLL) have suggested that one of the mechanisms of nitrogen mustard (NM) drug resistance is increased repair of drug-induced damage. We have postulated that recombination may play a crucial role in this process. The human homologue of Rad51, (HsRad51), has homology to the RecA protein in Escherichia coli, which is implicated in recombination repair and induction of DNA repair enzymes. In this report, we have examined the expression and distribution of HsRad51 protein in lymphocytes from patients with B-CLL to see whether the expression of HsRad51 is associated with NM damage to the malignant B lymphocytes, specifically chlorambucil (CLB), which is the standard alkylating agent used to treat patients with B-CLL. We have analyzed the intracellular distribution of HsRad51 protein in these lymphocytes before and after treatment with CLB by immunofluorescence. In vitro CLB treatment induces Rad51 expression, as measured by increased immunopositive staining in all CLL samples. In the CLB-resistant CLL lymphocytes, there was a linear correlation between induction of Rad51 protein at 5.4 microM CLB and the in vitro LD50 dose of CLB. Surprisingly, although it has been reported that Rad51 is induced in S phase and only 10% of cells from cell lines expressed positive immunostaining for Rad51, our CLL lymphocytes, which were not subjected to in vitro drug exposure, were 90% positive for Rad51, despite their nonproliferative state, which suggests that there is chronic activation of the protein. Our results suggest that CLB activates HsRad51-directed recombination repair and that this process may be important in NM drug-induced cytotoxicity.
- Published
- 1999
39. Enhanced antitumor activity of sarCNU in comparison to BCNU in an extraneuronal monoamine transporter positive human glioma xenograft model.
- Author
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Chen ZP, Wang G, Huang Q, Sun ZF, Zhou LY, Wang AD, and Panasci LC
- Subjects
- Animals, Disease Models, Animal, Drug Screening Assays, Antitumor, Female, Glioma chemically induced, Humans, Male, Mice, Mice, Nude, Transplantation, Heterologous, Tumor Cells, Cultured, Antineoplastic Agents therapeutic use, Carmustine analogs & derivatives, Carmustine therapeutic use, Carrier Proteins analysis, Glioma drug therapy, Organic Cation Transport Proteins
- Abstract
A novel analogue of nitrosoureas, 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU), has demonstrated increased anticancer effects in vitro and in vivo. Our previous work suggested that SarCNU enters cells via the extraneuronal monoamine transporter (EMT), that contributes to its enhanced cytotoxicity. In the present study, comparative activities of SarCNU and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were evaluated in an EMT positive human glioma xenograft model. Athymic nude mice implanted subcutaneously or intracranially with human glioma SHG-44, a cell line that has been confirmed EMT positive by using reverse-transcription polymerase chain reaction (RT-PCR) assay, were treated with SarCNU at an optimal dose of 167 mg/kg, or BCNU at 20 mg/kg or 30 mg/kg, q4d x 3 intraperitoneally (i.p.). In 17 animals with subcutaneous tumor grafts treated with SarCNU, 9 animals became tumor free and 8 demonstrated tumor regression. While in the BCNU treated group, there were only 2 out of 10 mice in the 20 mg/kg group and 2 out of 7 in the 30 mg/kg group, which demonstrated some tumor regression. There were 4 drug related deaths in the BCNU (30 mg/kg) group, while there were no drug related deaths in the SarCNU group. In the intracranially implanted mice, the median survival time in the SarCNU group was more than 130 days, while in the BCNU treated group it was only 22 days which was similar to the control group (18 days). This is the first demonstration that SarCNU, in comparison to BCNU, has enhanced anticancer activity in an EMT positive human glioma xenograft model.
- Published
- 1999
- Full Text
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40. Relationship between O6-methylguanine-DNA methyltransferase levels and clinical response induced by chloroethylnitrosourea therapy in glioma patients.
- Author
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Chen ZP, Yarosh D, Garcia Y, Tampieri D, Mohr G, Malapetsa A, Langleben A, and Panasci LC
- Subjects
- Adult, Age Factors, Aged, Brain Neoplasms drug therapy, Drug Resistance, Neoplasm genetics, Female, Glioma drug therapy, Guanine metabolism, Humans, Male, Middle Aged, Nitroso Compounds therapeutic use, Tumor Cells, Cultured metabolism, Antineoplastic Agents therapeutic use, Brain Neoplasms metabolism, DNA Modification Methylases metabolism, Glioma metabolism, Guanine analogs & derivatives
- Abstract
Background: Adjuvant nitrosourea chemotherapy fails to prolong survival significantly as many tumors demonstrate resistance to these drugs. It has been documented in cell lines that O6-methylguanine DNA methyltransferase (MGMT) plays an important role in chloroethylnitrosourea (CENU) drug resistance., Methods: We evaluated MGMT expression in 22 glioma specimens by using an immunofluorescence assay and compared the results with clinical responses of the patients to CENU-based chemotherapy., Results: Eight tumor samples had no detectable MGMT, whereas other samples had from 9,989 to 982,401 molecules/nucleus. In one group (12 patients), the tumor decreased in size or was stable (effective group), whereas in the other group (10 patients), the tumor demonstrated continuous growth during chemotherapy (progressive group). The Mer- patients (MGMT < 60,000 molecules/nucleus) appeared to have more chance of stable disease or response to CENU therapy than the Mer+ patients (MGMT > 60,000 molecules/nucleus) (X2 = 4.791, p = 0.0286). In patients with glioblastomas multiforme (GBMs), the median time to progression (TTP) of Mer+ patient was shorter than that of Mer- patient (t = 2.04, p = 0.049). As a corollary, the MGMT levels were significantly higher in GBM tumors from the progressive group than those from the effective group (t = 2.26, p = 0.029). However, there was no significant correlation between MGMT levels and either the survival time (r = 0.04, p = 0.8595) or TTP (r = 0.107, p = 0.6444)., Conclusion: This study suggests that being MGMT positive is indicative of a more aggressive disease that progresses more rapidly with CENU therapy. However, MGMT negative tumors are not always sensitive to CENU agents, suggesting that other factors are also important.
- Published
- 1999
41. Clodronate in metastatic breast cancer.
- Author
-
Panasci LC, Sandor V, and Melnychuk D
- Subjects
- Bone Neoplasms prevention & control, Bone Neoplasms secondary, Chemotherapy, Adjuvant, Female, Humans, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Clodronic Acid therapeutic use, Neoplasm Metastasis prevention & control
- Published
- 1998
42. Clinical response of O(6)-methylguanine-DNA methyltransferase levels to 1,3-(2-chloroethyl)-1-nitrosourea chemotherapy in glioma patients.
- Author
-
Chen ZP, Yarosh D, Garcia Y, Tampieri D, Mohr G, Langleben A, and Panasci LC
- Abstract
Adjuvant nitrosourea chemotherapy fails to prolong patient survival significantly as many tumors demonstrate resistance to these drugs. It has been documented in cell lines that O(6)-methylguanine-DNA methyltransferase (MGMT) plays an important role in chloroethylnitrosourea (CENU) drug resistance. The authors evaluated MGMT expression in 22 glioma specimens by using an immunofluorescence assay and compared the results with clinical response of the patients to CENU-based chemotherapy. The patients were treated with CENU after evidence of progressive disease following surgery and radiotherapy. Eight tumor samples had no detectable MGMT, whereas other samples had from 9989 to 982,401 molecules/nucleus. In one group (12 patients), the tumor decreased in size or was stable (effective group), whereas in the other group (10 patients), the tumor demonstrated continuous growth during chemotherapy (progressive group). The median time to progression (TTP) was 6.7 months with a median survival of 13 months. The Mer(-) patients (MGMT < 60,000 molecules/nucleus) appeared to have more chance of stable disease or response to CENU therapy than the Mer(+) patients (MGMT > 60,000 molecules/nucleus) (chi-square = 4.791, p = 0.0286). In patients with glioblastomas multiforme (GBMs), the TTP of Mer(+) patients was shorter than that of Mer(-) patients (t = 2.04, p = 0.049). As a corollary, the MGMT levels were significantly higher in GBM tumors from the progressive group than those from the effective group (t = -2.26, p = 0.029). The TTP and survival time in the effective GBM group were also longer than those in the progressive GBM group. However, there was no significant correlation between MGMT levels and either the survival time (r = 0.04, p = 0.8595) or TTP (r = 0.107, p = 0.6444). Results from this study suggested that MGMT positivity is indicative of more aggressive disease that progresses more rapidly when exposed to CENU therapy. However, MGMT-negative tumors are not always sensitive to CENU agents, suggesting that other factors may also be important.
- Published
- 1998
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43. Excision repair cross-complementing rodent repair deficiency gene 2 expression and chloroethylnitrosourea resistance in human glioma cell lines.
- Author
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Chen ZP, McQuillan A, Mohr G, and Panasci LC
- Subjects
- Brain Neoplasms genetics, Colorimetry, Genetic Complementation Test, Glioma genetics, Humans, Neoplasm Proteins biosynthesis, Polymerase Chain Reaction, Protein Biosynthesis, Tumor Cells, Cultured, Xeroderma Pigmentosum Group D Protein, Brain Neoplasms pathology, Carmustine analogs & derivatives, Carmustine pharmacology, DNA Helicases, DNA Repair genetics, DNA, Neoplasm genetics, DNA-Binding Proteins, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic drug effects, Glioma pathology, Neoplasm Proteins genetics, Proteins genetics, Transcription Factors
- Abstract
Objective: Nitrosoureas are the standard chemotherapeutic agents for malignant brain tumors. However, their anticancer effects are limited because many tumors are resistant to these agents. Nucleotide excision repair can repair bulky deoxyribonucleic acid adducts, including deoxyribonucleic acid damage induced by ultraviolet light and some chemotherapeutic agents, and may be implicated in nitrosoureas resistance. In this study, we compared excision repair cross-complementing rodent repair deficiency Gene 2 (ERCC2), an important component of the nucleotide excision repair system, with 1 ,3-bis-(2-chloroethyl)-1-nitrosourea or (2-chloroethyl)-3-sarcosinamide-1-nitrosourea resistance in human glioma cell lines., Methods: ERCC2 expression was evaluated by using established quantitative reverse-transcription polymerase chain reaction. 1,3-Bis-(2-chloroethyl)-1-nitrosourea and (2-chloroethyl)-3-sarcosinamide-1-nitrosourea cytotoxicity were determined by a modification of the sulforhodamine B colorimetric anticancer drug screening assay., Results: A significant correlation between ERCC2 expression and 1 ,3-bis-(2-chloroethyl)-1-nitrosourea or (2-chloroethyl)-3-sarcosinamide-1-nitrosourea cytotoxicity was determined (r=0.737, P=0.0226 and r=0.789, P=0.0113, respectively)., Conclusion: Our results suggest that nucleotide excision repair, specifically ERCC2, may play an important role in nitrosoureas drug resistance in human gliomas.
- Published
- 1998
- Full Text
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44. Re: five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors.
- Author
-
Panasci LC and Melnychuk D
- Subjects
- Age Factors, Breast Neoplasms metabolism, Breast Neoplasms pathology, Female, Follow-Up Studies, Humans, Lymphatic Metastasis, Middle Aged, Survival Analysis, Time Factors, Treatment Outcome, Antineoplastic Agents, Hormonal administration & dosage, Breast Neoplasms drug therapy, Estrogen Antagonists administration & dosage, Receptors, Estrogen drug effects, Tamoxifen administration & dosage
- Published
- 1997
- Full Text
- View/download PDF
45. Evidence for nucleotide excision repair as a modifying factor of O6-methylguanine-DNA methyltransferase-mediated innate chloroethylnitrosourea resistance in human tumor cell lines.
- Author
-
Chen ZP, Malapetsa A, McQuillan A, Marcantonio D, Bello V, Mohr G, Remack J, Brent TP, and Panasci LC
- Subjects
- Blotting, Western, Cell Count drug effects, Humans, O(6)-Methylguanine-DNA Methyltransferase drug effects, Proteins metabolism, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured radiation effects, Ultraviolet Rays, Xeroderma Pigmentosum Group D Protein, Antineoplastic Agents, Alkylating pharmacology, Carmustine pharmacology, DNA Helicases, DNA Repair genetics, DNA-Binding Proteins, O(6)-Methylguanine-DNA Methyltransferase genetics, Proteins genetics, Transcription Factors
- Abstract
We examined the O6-methylguanine-DNA methyltransferase (MGMT) protein as well as MGMT activity levels and the excision repair cross-complementing rodent repair deficiency gene, ERCC2 (XPD), protein levels in 14 human tumor cell lines not selected for chloroethylnitrosourea (CENU) resistance. These results were compared with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) cytotoxicity and UV light sensitivity. MGMT protein correlated significantly with MGMT activity (r = 0.9497, p = 0.0001). There was no significant linear correlation between BCNU cytotoxicity and MGMT content as determined by both Western analysis (r = 0.139, p = 0. 6348) and activity assay (r = 0.131, p = 0.6515). However, MGMT-rich cell lines were found to be more resistant than MGMT-poor cell lines to BCNU (t = 2.2375, p = 0.0225) but not to UV (t = 1.1734, p = 0.1317). Furthermore, the most BCNU-sensitive cell lines were all MGMT-poor. UV sensitivity was significantly correlated to BCNU cytotoxicity (r = 0.858, p = 0.0001). Significant correlations were found between ERCC2 protein levels and BCNU cytotoxicity (r = 0.786, p = 0.0009) or UV sensitivity (r = 0.874, p = 0.0001). Our results confirm that MGMT plays an important role in CENU resistance, but not in UV resistance. The correlation of UV sensitivity with BCNU cytotoxicity suggests that nucleotide excision repair is an important modifying factor of MGMT-mediated innate CENU resistance in human tumor cell lines, especially in highly resistant cell lines. ERCC2 may be implicated in this process.
- Published
- 1997
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46. 2-Chloroethyl-3-sarcosinamide-1-nitrosourea, a novel chloroethylnitrosourea analogue with enhanced antitumor activity against human glioma xenografts.
- Author
-
Marcantonio D, Panasci LC, Hollingshead MG, Alley MC, Camalier RF, Sausville EA, Dykes DJ, Carter CA, and Malspeis L
- Subjects
- Administration, Oral, Animals, Drug Administration Schedule, Female, Humans, Injections, Intraperitoneal, Male, Mice, Mice, Nude, Neoplasm Transplantation, Transplantation, Heterologous, Antineoplastic Agents, Alkylating administration & dosage, Carmustine administration & dosage, Carmustine analogs & derivatives, Glioma drug therapy
- Abstract
Nitrosoureas are among the most widely used agents used in the treatment of malignant gliomas. Here, the activity of 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) was compared with that of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), in vivo against s.c. implanted SF-295 and U-251 central nervous system (CNS) tumor xenografts. When given i.v., q4d for 3 doses, to athymic mice bearing s.c. SF-295 tumors, SarCNU, at an optimum of 167 mg/kg/dose, produced 9 tumor-free animals of 10 total animals, 1 regression, and no evidence of overt toxicity (> or =20% body weight loss). With a similar dosing schedule, BCNU produced no tumor-free animals, six regressions, and one drug-related death at its optimum of 30 mg/kg/dose. Furthermore, SarCNU retained high antitumor activity at two lower dose levels, 66 and 45% of the optimal dose, whereas BCNU demonstrated a progressive loss of antitumor activity at lower doses. Following p.o. administration, SarCNU similarly demonstrated antitumor activity that was superior to that of BCNU. In the U-251 CNS tumor model, SarCNU yielded six of six tumor-free animals at 80 mg/kg/dose with i.p. administration q.d. for 5 days, starting on day 14, whereas BCNU, at 9 mg/kg/dose, yielded three of six tumor-free mice and one drug-related death. Again, SarCNU resulted in tumor-free animals at 66 and 45% of its optimal dose and was relatively nontoxic, in contrast to BCNU. Results of testing to date indicate that SarCNU is clearly more effective than BCNU against the human CNS tumors SF-295 and U-251 in vivo. These results encourage the initiation of clinical trials for SarCNU, in an effort to improve therapeutic approaches to glioma, but clinical trials must determine whether superiority of SarCNU in preclinical models can be extrapolated to patients.
- Published
- 1997
47. Quantitation of ERCC-2 gene expression in human tumor cell lines by reverse transcription-polymerase chain reaction in comparison to northern blot analysis.
- Author
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Chen ZP, Malapetsa A, Mohr G, Brien S, and Panasci LC
- Subjects
- Actins analysis, Blotting, Northern, DNA Repair, Gene Expression, Glioma genetics, Humans, Polymerase Chain Reaction, Proteins genetics, Reproducibility of Results, Tumor Cells, Cultured metabolism, Xeroderma Pigmentosum Group D Protein, DNA Helicases, DNA-Binding Proteins, Proteins analysis, Transcription Factors
- Abstract
Excision repair cross-complementing rodent repair deficiency genes (ERCC) are human genes implicated in nucleotide excision repair. ERCC-2 has been implicated in the repair of DNA damaged by chemotherapeutic agents, and may thus play an important role in anticancer drug resistance. ERCC-2 gene expression is low in primary tumor samples rendering it difficult to quantitate. We have developed a semiquantitative method to measure ERCC-2 gene expression utilizing reverse transcription-polymerase chain reaction (RT-PCR). Total RNA extracted from established human tumor cell lines was reverse-transcribed to obtain cDNA. Serially diluted reference ERCC-2 DNA fragment was amplified by PCR to obtain a 617-bp fragment. A standard curve was then created using densitometry readings of the 617-bp bands on agarose gel. A fixed amount of sample cDNA from each cell line was amplified at the same time and the resultant PCR product was read by densitometer. Using the standard curve, ERCC-2 gene expression in a given amount of total RNA was quantitated and normalized to beta-actin expression. There was minimal variation in three repeated experiments with PCR amplification. ERCC-2 gene expression determined by this semiquantitative PCR was also correlated to ERCC-2 quantitation by Northern blot analysis, with a significant concordance (r = 0.912, P = 0.0002). We also successfully applied this sensitive method to quantify five clinical glioma samples.
- Published
- 1997
- Full Text
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48. Correlation of chloroethylnitrosourea resistance with ERCC-2 expression in human tumor cell lines as determined by quantitative competitive polymerase chain reaction.
- Author
-
Chen ZP, Malapetsa A, Marcantonio D, Mohr G, Brien S, and Panasci LC
- Subjects
- Antineoplastic Agents toxicity, Base Sequence, DNA Primers chemistry, Humans, Molecular Sequence Data, Polymerase Chain Reaction methods, RNA, Messenger genetics, Tumor Cells, Cultured, Xeroderma Pigmentosum Group D Protein, Carmustine analogs & derivatives, Carmustine toxicity, DNA Helicases, DNA-Binding Proteins, Drug Resistance, Gene Expression Regulation, Neoplastic, Proteins genetics, Transcription Factors
- Abstract
We have developed a method to quantitate ERCC-2 gene expression in tumor cell lines. A mutant ERCC-2 DNA fragment (1-bp mutation) is used as a competitive DNA template in a coamplification PCR reaction with cDNA obtained by reverse transcribing DNase-free total RNA from six human tumor cell lines. The PCR products are separated on agarose gel by virtue of their differential banding pattern upon restriction enzyme digestion. Densitometric readings of the PCR products from a negative film of the gel are used to establish a linear regression curve, which in turn is used to quantitate ERCC-2 levels. Beta-actin expression is similarly quantitated. Normalized ERCC-2 gene expression (either to beta-actin or to total RNA) correlates with cytotoxicity of 1,3-bis-(2-chloroethyl)-1-nitrosourea or (2-chloroethyl)-3-sarcosinamide-1-nitrosourea, suggesting that ERCC-2 may play an important role in drug resistance in these cell lines. This method is reliable and can be used to quantitate gene expression in clinical tumor specimens.
- Published
- 1996
49. Identification of a 116 kDa protein able to bind 1,3-bis(2-chloroethyl)-1-nitrosourea-damaged DNA as poly(ADP-ribose) polymerase.
- Author
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Malapetsa A, Noë AJ, Poirier GG, Desnoyers S, Berger NA, and Panasci LC
- Subjects
- Blotting, Southern, Blotting, Western, DNA Damage, DNA Probes, DNA, Neoplasm metabolism, Drug Resistance, Neoplasm, Electrophoresis, Polyacrylamide Gel methods, Glioma enzymology, Humans, NAD analysis, Poly(ADP-ribose) Polymerases analysis, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured enzymology, Antineoplastic Agents, Alkylating pharmacology, Carmustine pharmacology, DNA Repair physiology, DNA-Binding Proteins physiology, Poly(ADP-ribose) Polymerases metabolism
- Abstract
SKI-1 is a 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-resistant glioma cell line and SK-MG-1 is a BCNU-sensitive glioma cell line. Both cell lines do not express O6-methylguanine-DNA methyl transferase (MGMT) and exhibit comparable levels of 3-methyladenine DNA glycosylase. In order to detect DNA binding proteins involved in alternative DNA repair mechanisms of BCNU damage, we performed Southwestern analysis using a DNA probe damaged with BCNU and nuclear protein extracts from SKI-1 and SK-MG-1 cell lines. Both cell lines express a protein of M(r) 116,000 that is able to bind to BCNU-damaged DNA with higher specificity than to undamaged DNA. This protein was identified as poly(ADP-ribose) polymerase (PARP). Using glioma extracts depleted of PARP or using antibody to block the DNA binding domain of PARP no other protein binding to BCNU-treated probe was observed. Addition of methoxyamine, an inhibitor of DNA strand breaks, led to a significant reduction of PARP binding to BCNU-treated DNA. BCNU treatment of both glioma cell lines led to reduced nicotinamide adenine dinucleotide levels, indicating activation of PARP. Thus, the recognition and binding of PARP to BCNU-induced DNA nicks with concomitant PARP activation may be important processes that are involved in the initial stage of DNA repair of BCNU lesions in glial cells.
- Published
- 1996
- Full Text
- View/download PDF
50. Nitrogen mustard drug resistant B-cell chronic lymphocytic leukemia as an in vivo model for crosslinking agent resistance.
- Author
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Bramson J, McQuillan A, Aubin R, Alaoui-Jamali M, Batist G, Christodoulopoulos G, and Panasci LC
- Subjects
- B-Lymphocytes drug effects, B-Lymphocytes radiation effects, Chlorambucil pharmacology, Cisplatin pharmacology, DNA Adducts, DNA Damage, Drug Resistance genetics, Drug Resistance physiology, Humans, Inactivation, Metabolic, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Melphalan pharmacology, Methyl Methanesulfonate pharmacology, Mitomycin pharmacology, Nitrogen Mustard Compounds metabolism, Nitrogen Mustard Compounds therapeutic use, Tetrazolium Salts, Thiazoles, Tumor Cells, Cultured drug effects, Cross-Linking Reagents pharmacology, DNA Repair physiology, DNA, Neoplasm drug effects, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Nitrogen Mustard Compounds pharmacology
- Abstract
Acquired resistance is a limiting factor in chemotherapy. We have employed nitrogen mustard resistant B-cell chronic lymphocytic leukemia (B-CLL) as a clinically relevant model to study this phenomenon. Resistance in B-CLL is associated with enhanced repair of nitrogen mustard crosslinks. In order to identify the repair pathway responsible for nitrogen mustard resistance, lymphocytes were screened for cross-resistance to a variety of DNA damaging agents. The MTT assay was used to measure the resistance of B-CLL lymphocytes to various DNA damaging agents, including nitrogen mustards, UV light, methyl methanesulfonate, and mitomycin C. We have shown that B lymphocytes from patients with nitrogen mustard resistant chronic lymphocytic leukemia reflect their clinical status. This assay allows us to classify lymphocytes as nitrogen mustard sensitive or resistant, based on in vitro observations. The resistant population was 5.6 and 4.1 fold more resistant to the nitrogen mustard analogs, chlorambucil and melphalan, respectively. Resistant lymphocytes displayed no increased resistance to either methyl methanesulfonate or UV light, indicating that neither classical base nor nucleotide excision repair is rate-limiting in resistance. Resistant lymphocytes were 6.0 and 2.2 fold more resistant to mitomycin C and cis-diamminedichloroplatinum (II), respectively, suggesting enhanced crosslink repair. Neither glutathione nor glutathione S-transferase levels correlated with resistance. The development of nitrogen mustard drug resistance in B-CLL appears to be associated with cross-resistance to other bifunctional alkylating agents which produce interstrand crosslinks. Our results indicate that resistance to nitrogen mustards in chronic lymphocytic leukemia is associated with enhanced repair of DNA crosslinks which may involve a recombination dependent system. This model should prove very useful in the elucidation of the molecular mechanisms of crosslink repair.
- Published
- 1995
- Full Text
- View/download PDF
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