Targeted Apoptosis Activation with GrB/scFvMEL Modulates Melanoma Growth, Metastatic Spread, Chemosensitivity, and Radiosensitivity
GrB/scFvMEL, a fusion protein composed of human granzyme B (GrB) and the single-chain antibody scFvMEL, targets melanoma gp240 antigen and exerts impressive cytotoxic effects by inducing apoptosis. We evaluated the effects of GrB/scFvMEL on chemotherapy, radiation therapy, metastasis in vitro, and t...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2006-02-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558606800217 |
| _version_ | 1811318769889312768 |
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| author | Yuying Liu Weihe Zhang Ting Niu Lawrence H. Cheung Anupama Munshi Raymond E. Meyn, Jr. Michael G. Rosenblum |
| author_facet | Yuying Liu Weihe Zhang Ting Niu Lawrence H. Cheung Anupama Munshi Raymond E. Meyn, Jr. Michael G. Rosenblum |
| author_sort | Yuying Liu |
| collection | DOAJ |
| description | GrB/scFvMEL, a fusion protein composed of human granzyme B (GrB) and the single-chain antibody scFvMEL, targets melanoma gp240 antigen and exerts impressive cytotoxic effects by inducing apoptosis. We evaluated the effects of GrB/scFvMEL on chemotherapy, radiation therapy, metastasis in vitro, and the growth of human melanoma A375 xenograft tumors in nude mice. GrB/scFvMEL showed synergistic cytotoxicity when coadministered with doxorubicin, vincristine or cisplatin, and additive effects, in combination with etoposide or cytarabine. Optimal cytotoxic effects were obtained when cells were treated first with GrB/scFvMEL followed by exposure to the agent (rather than the reverse). Pretreatment of A375 cells with GrB/scFvMEL significantly sensitized melanoma cells to ionizing radiation assessed using a clonogenic survival assay. Subtoxic doses of GrB/scFvMEL inhibited the invasion of A375 cells into Matrigel. GrB/scFvMEL (37.5 mg/kg) was administered intravenously to nude mice bearing A375 tumors. Saline-treated tumors increased 24-fold, whereas tumors treated with GrB/scFvMEL showed a significant tumor growth delay increasing four-fold. Tumor tissue displayed an increase in apoptotic nuclei compared to control. Thus, the targeted delivery of GrB to tumors may have a significant potential for cancer treatment. Targeted therapeutic agents specifically designed to impact cellular apoptotic pathways may represent a novel class of therapeutic agents. |
| first_indexed | 2024-04-13T12:31:16Z |
| format | Article |
| id | doaj.art-f041274ac6364b4287e61f0ac3b47960 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-04-13T12:31:16Z |
| publishDate | 2006-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-f041274ac6364b4287e61f0ac3b479602022-12-22T02:46:51ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022006-02-018212513510.1593/neo.05556Targeted Apoptosis Activation with GrB/scFvMEL Modulates Melanoma Growth, Metastatic Spread, Chemosensitivity, and RadiosensitivityYuying Liu0Weihe Zhang1Ting Niu2Lawrence H. Cheung3Anupama Munshi4Raymond E. Meyn, Jr.5Michael G. Rosenblum6Immunopharmacology and Targeted Therapy Section, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USAImmunopharmacology and Targeted Therapy Section, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USADepartment of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, ChinaImmunopharmacology and Targeted Therapy Section, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USADepartment of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USADepartment of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USAImmunopharmacology and Targeted Therapy Section, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USAGrB/scFvMEL, a fusion protein composed of human granzyme B (GrB) and the single-chain antibody scFvMEL, targets melanoma gp240 antigen and exerts impressive cytotoxic effects by inducing apoptosis. We evaluated the effects of GrB/scFvMEL on chemotherapy, radiation therapy, metastasis in vitro, and the growth of human melanoma A375 xenograft tumors in nude mice. GrB/scFvMEL showed synergistic cytotoxicity when coadministered with doxorubicin, vincristine or cisplatin, and additive effects, in combination with etoposide or cytarabine. Optimal cytotoxic effects were obtained when cells were treated first with GrB/scFvMEL followed by exposure to the agent (rather than the reverse). Pretreatment of A375 cells with GrB/scFvMEL significantly sensitized melanoma cells to ionizing radiation assessed using a clonogenic survival assay. Subtoxic doses of GrB/scFvMEL inhibited the invasion of A375 cells into Matrigel. GrB/scFvMEL (37.5 mg/kg) was administered intravenously to nude mice bearing A375 tumors. Saline-treated tumors increased 24-fold, whereas tumors treated with GrB/scFvMEL showed a significant tumor growth delay increasing four-fold. Tumor tissue displayed an increase in apoptotic nuclei compared to control. Thus, the targeted delivery of GrB to tumors may have a significant potential for cancer treatment. Targeted therapeutic agents specifically designed to impact cellular apoptotic pathways may represent a novel class of therapeutic agents.http://www.sciencedirect.com/science/article/pii/S1476558606800217Granzyme Bsingle-chain Fv antibodyimmunotoxinapoptosismelanoma |
| spellingShingle | Yuying Liu Weihe Zhang Ting Niu Lawrence H. Cheung Anupama Munshi Raymond E. Meyn, Jr. Michael G. Rosenblum Targeted Apoptosis Activation with GrB/scFvMEL Modulates Melanoma Growth, Metastatic Spread, Chemosensitivity, and Radiosensitivity Neoplasia: An International Journal for Oncology Research Granzyme B single-chain Fv antibody immunotoxin apoptosis melanoma |
| title | Targeted Apoptosis Activation with GrB/scFvMEL Modulates Melanoma Growth, Metastatic Spread, Chemosensitivity, and Radiosensitivity |
| title_full | Targeted Apoptosis Activation with GrB/scFvMEL Modulates Melanoma Growth, Metastatic Spread, Chemosensitivity, and Radiosensitivity |
| title_fullStr | Targeted Apoptosis Activation with GrB/scFvMEL Modulates Melanoma Growth, Metastatic Spread, Chemosensitivity, and Radiosensitivity |
| title_full_unstemmed | Targeted Apoptosis Activation with GrB/scFvMEL Modulates Melanoma Growth, Metastatic Spread, Chemosensitivity, and Radiosensitivity |
| title_short | Targeted Apoptosis Activation with GrB/scFvMEL Modulates Melanoma Growth, Metastatic Spread, Chemosensitivity, and Radiosensitivity |
| title_sort | targeted apoptosis activation with grb scfvmel modulates melanoma growth metastatic spread chemosensitivity and radiosensitivity |
| topic | Granzyme B single-chain Fv antibody immunotoxin apoptosis melanoma |
| url | http://www.sciencedirect.com/science/article/pii/S1476558606800217 |
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