Targeted apoptosis activation with GrB/scFvMEL modulates melanoma growth, metastatic spread, chemosensitivity, and radiosensitivity

Yuying Liu; Weihe Zhang; Ting Niu; Lawrence H. Cheung; Anupama Munshi; Raymond E. Meyn; Michael G. Rosenblum

doi:10.1593/neo.05556

Targeted apoptosis activation with GrB/scFvMEL modulates melanoma growth, metastatic spread, chemosensitivity, and radiosensitivity

Yuying Liu, Weihe Zhang, Ting Niu, Lawrence H. Cheung, Anupama Munshi, Raymond E. Meyn, Michael G. Rosenblum

Experimental Therapeutics

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	125-135
Number of pages	11
Journal	Neoplasia
Volume	8
Issue number	2
DOIs	https://doi.org/10.1593/neo.05556
State	Published - Feb 2006

Keywords

Apoptosis
Granzyme B
Immunotoxin
Melanoma
Single-chain Fv antibody

ASJC Scopus subject areas

Cancer Research

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10.1593/neo.05556

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@article{c7bb7818212743c581b1d6b6304b9340,

title = "Targeted apoptosis activation with GrB/scFvMEL modulates melanoma growth, metastatic spread, chemosensitivity, and radiosensitivity",

abstract = "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.",

keywords = "Apoptosis, Granzyme B, Immunotoxin, Melanoma, Single-chain Fv antibody",

author = "Yuying Liu and Weihe Zhang and Ting Niu and Cheung, {Lawrence H.} and Anupama Munshi and Meyn, {Raymond E.} and Rosenblum, {Michael G.}",

note = "Funding Information: Abbreviations: GrB, human granzyme B; scFv, recombinant single-chain Fv antibody; rGel, recombinant gelonin; A375DR, A375 doxorubicin–resistant Address all correspondence to: Michael G. Rosenblum, PhD, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Unit 44, 1515 Hol-combe Boulevard, Houston, TX 77030. E-mail: mrosenbl@mdanderson.org 1This research was supported, in part, by the Clayton Foundation for Research. Received 25 August 2005; Revised 18 November 2005; Accepted 21 November 2005.",

year = "2006",

month = feb,

doi = "10.1593/neo.05556",

language = "English (US)",

volume = "8",

pages = "125--135",

journal = "Neoplasia",

issn = "1522-8002",

publisher = "Elsevier Inc.",

number = "2",

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T1 - Targeted apoptosis activation with GrB/scFvMEL modulates melanoma growth, metastatic spread, chemosensitivity, and radiosensitivity

AU - Liu, Yuying

AU - Zhang, Weihe

AU - Niu, Ting

AU - Cheung, Lawrence H.

AU - Munshi, Anupama

AU - Meyn, Raymond E.

AU - Rosenblum, Michael G.

N1 - Funding Information: Abbreviations: GrB, human granzyme B; scFv, recombinant single-chain Fv antibody; rGel, recombinant gelonin; A375DR, A375 doxorubicin–resistant Address all correspondence to: Michael G. Rosenblum, PhD, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Unit 44, 1515 Hol-combe Boulevard, Houston, TX 77030. E-mail: mrosenbl@mdanderson.org 1This research was supported, in part, by the Clayton Foundation for Research. Received 25 August 2005; Revised 18 November 2005; Accepted 21 November 2005.

PY - 2006/2

Y1 - 2006/2

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Granzyme B

KW - Immunotoxin

KW - Melanoma

KW - Single-chain Fv antibody

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Targeted apoptosis activation with GrB/scFvMEL modulates melanoma growth, metastatic spread, chemosensitivity, and radiosensitivity

Abstract

Keywords

ASJC Scopus subject areas

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