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Zou, Yiyu; Zong, Gang; Ling, Yi-He; Hao, Ming Ming; Lozano, Guillermina; Hong, Waun K.; Perez-Soler, Roman
doi: 10.1093/jnci/90.15.1130pmid: 9701362
AbstractBackground: Lung cancer originates in a diffusely damaged bronchial epithelium as a result of sequential and cumulative genetic alterations. We investigated the feasibility of in vivogene replacement in endobronchial precancerous and cancerous cells by a regionally administered nonviral delivery system. Methods: After evaluating the in vitrotransfection efficiency and cytotoxicity of a variety of cationic liposome- p53 formulations, a specific formulation, DP3-p53, was selected for further in vitroand in vivoevaluation. The ability of DP3-p53 to introduce the p53 gene in the normal bronchial epithelium was studied in transgenic mice that lack the p53 gene. The therapeutic effect of DP3-p53 administered intratracheally was studied in two nude mouse models of endobronchial human lung cancer by use of H358 (p53-null) and H322 (p53-mutant) cells. Results: DP3-p53 was able to effectively introduce and express the p53 gene and induce G1 arrest and apoptosis in H358 cells in vitroand to introduce and transcribe the p53 gene in the bronchial epithelium of transgenic mice that lack the p53 gene in vivo. In therapeutic experiments using groups of four or five mice each, administration of five intratracheal doses of DP3-p53 (2 µg or 8 µg DNA per dose) on days 4, 8, 12, 16, and 20 after intratracheal tumor inoculation significantly inhibited lung tumor formation and prolonged by approximately twofold the survival of mice bearing H358 or H322 endobronchial tumor cells in contrast to the survival among untreated mice and mice treated with the DP3-empty vector (P = .007 [two-sided logrank test] for mice bearing H358 cells and P = .008 [twosided logrank test] for those bearing H322 cells). Conclusions/ Implications: Liposome-based p53 delivery through the airways is a potentially effective strategy for the treatment of early endobronchial cancer. These results have important implications for the gene therapy and prevention of human lung cancer. [J Natl Cancer Inst 1998;90:1130-7]
Zou, Yiyu; Zong, Gang; Ling, Yi-He; Hao, Ming Ming; Lozano, Guillermina; Hong, Waun K.; Perez-Soler, Roman
doi: N/Apmid: N/A
Background: Lung cancer originates in a diffusely damaged bronchial epithelium as a result of sequential and cumulative genetic alterations. We investigated the feasibility of in vivo gene replacement in endobronchial precancerous and cancerous cells by a regionally administered nonviral delivery system. Methods: After evaluating the in vitro transfection efficiency and cytotoxicity of a variety of cationic liposome- p53 formulations, a specific formulation, DP3-p53, was selected for further in vitro and in vivo evaluation. The ability of DP3-p53 to introduce the p53 gene in the normal bronchial epithelium was studied in transgenic mice that lack the p53 gene. The therapeutic effect of DP3-p53 administered intratracheally was studied in two nude mouse models of endobronchial human lung cancer by use of H358 (p53-null) and H322 (p53-mutant) cells. Results: DP3-p53 was able to effectively introduce and express the p53 gene and induce G1 arrest and apoptosis in H358 cells in vitro and to introduce and transcribe the p53 gene in the bronchial epithelium of transgenic mice that lack the p53 gene in vivo. In therapeutic experiments using groups of four or five mice each, administration of five intratracheal doses of DP3-p53 (2 µg or 8 µg DNA per dose) on days 4, 8, 12, 16, and 20 after intratracheal tumor inoculation significantly inhibited lung tumor formation and prolonged by approximately twofold the survival of mice bearing H358 or H322 endobronchial tumor cells in contrast to the survival among untreated mice and mice treated with the DP3-empty vector (P = .007 [two-sided logrank test] for mice bearing H358 cells and P = .008 [twosided logrank test] for those bearing H322 cells). Conclusions/ Implications: Liposome-based p53 delivery through the airways is a potentially effective strategy for the treatment of early endobronchial cancer. These results have important implications for the gene therapy and prevention of human lung cancer. [J Natl Cancer Inst 1998;90:1130-7]
Lakhani, Sunil R.; Jacquemier, Jocelyne; Sloane, John P.; Gusterson, Barry A.; Anderson, Thomas J.; van de Vijver, Marc J.; Farid, Linda M.; Venter, Deon; Antoniou, Antonios; Storfer-Isser, Amy; Smyth, Elizabeth; Steel, C. Michael; Haites, Neva; Scott,, Rodney J.;
Lakhani, Sunil R.; Jacquemier, Jocelyne; Sloane, John P.; Gusterson, Barry A.; Anderson, Thomas J.; van de Vijver, Marc J.; Farid, Linda M.; Venter, Deon; Antoniou, Antonios; Storfer-Isser, Amy; Smyth, Elizabeth; Steel, C. Michael; Haites, Neva; Scott,, Rodney J.;
Smith, Janet B.; Wickstrom, Eric
doi: 10.1093/jnci/90.15.1146pmid: 9701364
AbstractBackground: Because the development of drug-resistant cells can lead to relapses in patients with lymphoma treated with chemotherapy, new approaches are needed for effective disease management, such as those targeting the c-MYC protooncogene with antisense oligonucleotides. Our goal was to investigate whether antisense c-myc oligonucleotides could prevent tumorigenesis in a B-cell lymphoma model. Methods: Immunocompetent mice received subcutaneous injections of tumor cells from a transgenic mouse model of Burkitt's lymphoma. For 7 consecutive days, beginning 1 day after tumor cell transplantation, the mice were given either a DNA phosphorothioate oligonucleotide complementary to c-myc codons 1–5 (myc6) or other c-myc-related oligonucleotides at a dose of 0.76 mg per day subcutaneously. Myc protein expression, normalized to b-actin expression, was measured by western blotting of tumor and splenic proteins. To determine whether tumor inhibition by myc6 could be a result of B-cell activation, we compared the activity of myc6 with that of an immunostimulatory oligonucleotide, mcg. Results: In comparison with control treatments (saline vehicle, scrambled-sequence oligonucleotide, or double-mismatch oligonucleotide), treatment with myc6 delayed tumor onset by 3 days, decreased total tumor mass at sacrifice (i.e., 17 days after tumor cell transplantation) by 40% ± 16% (mean ± standard error), and decreased the splenic Myc-to-actin ratio. Inhibition of tumors by myc6 and mcg (both of which share a dACGTT motif) was comparable. Administration of an oligonucleotide sequence complementary to c-myc codons 384–388 (myc55) delayed tumor onset by 5–6 days, decreased total tumor mass at sacrifice by 65% ± 6%, and reduced the splenic Myc-to-actin ratio to below that produced by myc6. A 14-day treatment regimen of myc55 alternating with mcg completely inhibited tumor formation during the therapeutic schedule. Conclusions: A combined oligonucleotide regimen, based on antisense c-MYC and immunostimulatory oligonucleotides, should be investigated to increase the number and duration of complete remissions obtained after standard chemotherapy for B-cell lymphoma. [J Natl Cancer Inst 1998;90:1146–54]
Smith, Janet B.; Wickstrom, Eric
doi: N/Apmid: N/A
Background: Because the development of drug-resistant cells can lead to relapses in patients with lymphoma treated with chemotherapy, new approaches are needed for effective disease management, such as those targeting the c-MYC protooncogene with antisense oligonucleotides. Our goal was to investigate whether antisense c-myc oligonucleotides could prevent tumorigenesis in a B-cell lymphoma model. Methods: Immunocompetent mice received subcutaneous injections of tumor cells from a transgenic mouse model of Burkitt's lymphoma. For 7 consecutive days, beginning 1 day after tumor cell transplantation, the mice were given either a DNA phosphorothioate oligonucleotide complementary to c-myc codons 1–5 (myc6) or other c-myc-related oligonucleotides at a dose of 0.76 mg per day subcutaneously. Myc protein expression, normalized to b-actin expression, was measured by western blotting of tumor and splenic proteins. To determine whether tumor inhibition by myc6 could be a result of B-cell activation, we compared the activity of myc6 with that of an immunostimulatory oligonucleotide, mcg. Results: In comparison with control treatments (saline vehicle, scrambled-sequence oligonucleotide, or double-mismatch oligonucleotide), treatment with myc6 delayed tumor onset by 3 days, decreased total tumor mass at sacrifice (i.e., 17 days after tumor cell transplantation) by 40% ± 16% (mean ± standard error), and decreased the splenic Myc-to-actin ratio. Inhibition of tumors by myc6 and mcg (both of which share a dACGTT motif) was comparable. Administration of an oligonucleotide sequence complementary to c-myc codons 384–388 (myc55) delayed tumor onset by 5–6 days, decreased total tumor mass at sacrifice by 65% ± 6%, and reduced the splenic Myc-to-actin ratio to below that produced by myc6. A 14-day treatment regimen of myc55 alternating with mcg completely inhibited tumor formation during the therapeutic schedule. Conclusions: A combined oligonucleotide regimen, based on antisense c-MYC and immunostimulatory oligonucleotides, should be investigated to increase the number and duration of complete remissions obtained after standard chemotherapy for B-cell lymphoma. [J Natl Cancer Inst 1998;90:1146–54]
Showing 1 to 10 of 26 Articles
doi: N/Apmid: N/A
Background: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. Methods: Specimens of tumor tissue (5-µm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. Results: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. Conclusions: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients. [J Natl Cancer Inst 1998;90:1138–45]
doi: 10.1093/jnci/90.15.1138pmid: 9701363
AbstractBackground: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. Methods: Specimens of tumor tissue (5-µm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. Results: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. Conclusions: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients. [J Natl Cancer Inst 1998;90:1138–45]