Conditionally replicating adenovirus-mediated gene therapy in bladder cancer: An orthotopic in vivo model

Jonathan J. Melquist; Michael Kacka; Yingming Li; Bahaa S. Malaeb; James Elmore; Adam G. Baseman; Jer Tsong Hsieh; Kenneth S. Koeneman

doi:10.1016/j.urolonc.2005.11.028

Conditionally replicating adenovirus-mediated gene therapy in bladder cancer: An orthotopic in vivo model

Jonathan J. Melquist, Michael Kacka, Yingming Li, Bahaa S. Malaeb, James Elmore, Adam G. Baseman, Jer Tsong Hsieh, Kenneth S. Koeneman

Research output: Contribution to journal › Review article › peer-review

10 Scopus citations

Abstract

Introduction: The effects of a conditionally replicating adenovirus on various bladder cancer lines were explored, a truncated bone sialoprotein (BSP) promoter controlling the E1a/b lytic-regulating sequence was used, since BSP protein is found in many osteotropic neoplasms, including bladder cancer. Methods: Reverse transcriptase polymerase chain reaction analysis was used to determine expression patterns of BSP and Coxsackie adenovirus receptor, a receptor known to interact with adenovirus, on multiple lines of bladder cancer (253J, 253J B-V, RT4, transitional cell carcinoma, T24, UMUC3, and WH). Ad-BSP-E1a was tested in vitro for lytic activity on 4 of these cell lines. The 253J B-V cell line was used and inoculated into female nude mice either subcutaneously in the flank or orthotopically into the bladder, and treated with control or Ad-BSP-E1a virus. Results: BSP is expressed in RT4, transitional cell carcinoma, and WH. Meanwhile, Coxsackie adenovirus receptor was expressed in all lines except T24. Ad-BSP-E1a had the most impact on 253J and 253J B-V cells; cell density declined significantly when compared to phosphate-buffered saline and Ad-BSP-TK "dummy" virus-treatment groups. The 253J B-V tumors treated with Ad-BSP-E1a revealed a decreased percent change of size in the subcutaneous model when compared to controls at week 3. The orthotopic murine model showed decreased end tumor mass in the Ad-BSP-E1a treated group over controls. Histologic examination of in vivo tumors showed evidence of fibrosis and apoptosis in the Ad-BSP-E1a treated groups using hematoxylin-eosin, trichrome, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining. Control groups only had viable tumor in in vivo models. Conclusion: Adenovirus therapy of orthotopic murine bladder tumors is feasible. Ad-BSP-E1a is effective in treating very aggressive yet sensitive bladder tumor cells. Further study of this conditionally replicating adenovirus treatment (Ad-BSP-E1a) with chemotherapeutic combination is warranted, and future translation of such combination therapy into human beings is a possibility.

Original language	English (US)
Pages (from-to)	362-371
Number of pages	10
Journal	Urologic Oncology: Seminars and Original Investigations
Volume	24
Issue number	4 SPEC. ISS.
DOIs	https://doi.org/10.1016/j.urolonc.2005.11.028
State	Published - 2006

Bibliographical note

Funding Information:
This work was supported by the United States Department of Defense. DOD award DAMD 17-01-1-0107 and DAMD 17-02-1-0148 and DOD Consortium Award DOD PCRP-02 indirectly helped complete these bladder cancer studies, which employed reagents developed for and during the aforementioned DOD prostate cancer research studies. Dr. Koeneman received the Dougherty Family Chair in Uro-Oncology.

Keywords

Adenoviral vectors
Bladder cancer
Bone sialoprotein
Cancer cell lines
Gene therapy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.urolonc.2005.11.028

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title = "Conditionally replicating adenovirus-mediated gene therapy in bladder cancer: An orthotopic in vivo model",

abstract = "Introduction: The effects of a conditionally replicating adenovirus on various bladder cancer lines were explored, a truncated bone sialoprotein (BSP) promoter controlling the E1a/b lytic-regulating sequence was used, since BSP protein is found in many osteotropic neoplasms, including bladder cancer. Methods: Reverse transcriptase polymerase chain reaction analysis was used to determine expression patterns of BSP and Coxsackie adenovirus receptor, a receptor known to interact with adenovirus, on multiple lines of bladder cancer (253J, 253J B-V, RT4, transitional cell carcinoma, T24, UMUC3, and WH). Ad-BSP-E1a was tested in vitro for lytic activity on 4 of these cell lines. The 253J B-V cell line was used and inoculated into female nude mice either subcutaneously in the flank or orthotopically into the bladder, and treated with control or Ad-BSP-E1a virus. Results: BSP is expressed in RT4, transitional cell carcinoma, and WH. Meanwhile, Coxsackie adenovirus receptor was expressed in all lines except T24. Ad-BSP-E1a had the most impact on 253J and 253J B-V cells; cell density declined significantly when compared to phosphate-buffered saline and Ad-BSP-TK {"}dummy{"} virus-treatment groups. The 253J B-V tumors treated with Ad-BSP-E1a revealed a decreased percent change of size in the subcutaneous model when compared to controls at week 3. The orthotopic murine model showed decreased end tumor mass in the Ad-BSP-E1a treated group over controls. Histologic examination of in vivo tumors showed evidence of fibrosis and apoptosis in the Ad-BSP-E1a treated groups using hematoxylin-eosin, trichrome, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining. Control groups only had viable tumor in in vivo models. Conclusion: Adenovirus therapy of orthotopic murine bladder tumors is feasible. Ad-BSP-E1a is effective in treating very aggressive yet sensitive bladder tumor cells. Further study of this conditionally replicating adenovirus treatment (Ad-BSP-E1a) with chemotherapeutic combination is warranted, and future translation of such combination therapy into human beings is a possibility.",

keywords = "Adenoviral vectors, Bladder cancer, Bone sialoprotein, Cancer cell lines, Gene therapy",

author = "Melquist, {Jonathan J.} and Michael Kacka and Yingming Li and Malaeb, {Bahaa S.} and James Elmore and Baseman, {Adam G.} and Hsieh, {Jer Tsong} and Koeneman, {Kenneth S.}",

note = "Funding Information: This work was supported by the United States Department of Defense. DOD award DAMD 17-01-1-0107 and DAMD 17-02-1-0148 and DOD Consortium Award DOD PCRP-02 indirectly helped complete these bladder cancer studies, which employed reagents developed for and during the aforementioned DOD prostate cancer research studies. Dr. Koeneman received the Dougherty Family Chair in Uro-Oncology. ",

year = "2006",

doi = "10.1016/j.urolonc.2005.11.028",

language = "English (US)",

volume = "24",

pages = "362--371",

journal = "Urologic Oncology: Seminars and Original Investigations",

issn = "1078-1439",

publisher = "Elsevier Inc.",

number = "4 SPEC. ISS.",

}

TY - JOUR

T1 - Conditionally replicating adenovirus-mediated gene therapy in bladder cancer

T2 - An orthotopic in vivo model

AU - Melquist, Jonathan J.

AU - Kacka, Michael

AU - Li, Yingming

AU - Malaeb, Bahaa S.

AU - Elmore, James

AU - Baseman, Adam G.

AU - Hsieh, Jer Tsong

AU - Koeneman, Kenneth S.

N1 - Funding Information: This work was supported by the United States Department of Defense. DOD award DAMD 17-01-1-0107 and DAMD 17-02-1-0148 and DOD Consortium Award DOD PCRP-02 indirectly helped complete these bladder cancer studies, which employed reagents developed for and during the aforementioned DOD prostate cancer research studies. Dr. Koeneman received the Dougherty Family Chair in Uro-Oncology.

PY - 2006

Y1 - 2006

N2 - Introduction: The effects of a conditionally replicating adenovirus on various bladder cancer lines were explored, a truncated bone sialoprotein (BSP) promoter controlling the E1a/b lytic-regulating sequence was used, since BSP protein is found in many osteotropic neoplasms, including bladder cancer. Methods: Reverse transcriptase polymerase chain reaction analysis was used to determine expression patterns of BSP and Coxsackie adenovirus receptor, a receptor known to interact with adenovirus, on multiple lines of bladder cancer (253J, 253J B-V, RT4, transitional cell carcinoma, T24, UMUC3, and WH). Ad-BSP-E1a was tested in vitro for lytic activity on 4 of these cell lines. The 253J B-V cell line was used and inoculated into female nude mice either subcutaneously in the flank or orthotopically into the bladder, and treated with control or Ad-BSP-E1a virus. Results: BSP is expressed in RT4, transitional cell carcinoma, and WH. Meanwhile, Coxsackie adenovirus receptor was expressed in all lines except T24. Ad-BSP-E1a had the most impact on 253J and 253J B-V cells; cell density declined significantly when compared to phosphate-buffered saline and Ad-BSP-TK "dummy" virus-treatment groups. The 253J B-V tumors treated with Ad-BSP-E1a revealed a decreased percent change of size in the subcutaneous model when compared to controls at week 3. The orthotopic murine model showed decreased end tumor mass in the Ad-BSP-E1a treated group over controls. Histologic examination of in vivo tumors showed evidence of fibrosis and apoptosis in the Ad-BSP-E1a treated groups using hematoxylin-eosin, trichrome, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining. Control groups only had viable tumor in in vivo models. Conclusion: Adenovirus therapy of orthotopic murine bladder tumors is feasible. Ad-BSP-E1a is effective in treating very aggressive yet sensitive bladder tumor cells. Further study of this conditionally replicating adenovirus treatment (Ad-BSP-E1a) with chemotherapeutic combination is warranted, and future translation of such combination therapy into human beings is a possibility.

AB - Introduction: The effects of a conditionally replicating adenovirus on various bladder cancer lines were explored, a truncated bone sialoprotein (BSP) promoter controlling the E1a/b lytic-regulating sequence was used, since BSP protein is found in many osteotropic neoplasms, including bladder cancer. Methods: Reverse transcriptase polymerase chain reaction analysis was used to determine expression patterns of BSP and Coxsackie adenovirus receptor, a receptor known to interact with adenovirus, on multiple lines of bladder cancer (253J, 253J B-V, RT4, transitional cell carcinoma, T24, UMUC3, and WH). Ad-BSP-E1a was tested in vitro for lytic activity on 4 of these cell lines. The 253J B-V cell line was used and inoculated into female nude mice either subcutaneously in the flank or orthotopically into the bladder, and treated with control or Ad-BSP-E1a virus. Results: BSP is expressed in RT4, transitional cell carcinoma, and WH. Meanwhile, Coxsackie adenovirus receptor was expressed in all lines except T24. Ad-BSP-E1a had the most impact on 253J and 253J B-V cells; cell density declined significantly when compared to phosphate-buffered saline and Ad-BSP-TK "dummy" virus-treatment groups. The 253J B-V tumors treated with Ad-BSP-E1a revealed a decreased percent change of size in the subcutaneous model when compared to controls at week 3. The orthotopic murine model showed decreased end tumor mass in the Ad-BSP-E1a treated group over controls. Histologic examination of in vivo tumors showed evidence of fibrosis and apoptosis in the Ad-BSP-E1a treated groups using hematoxylin-eosin, trichrome, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining. Control groups only had viable tumor in in vivo models. Conclusion: Adenovirus therapy of orthotopic murine bladder tumors is feasible. Ad-BSP-E1a is effective in treating very aggressive yet sensitive bladder tumor cells. Further study of this conditionally replicating adenovirus treatment (Ad-BSP-E1a) with chemotherapeutic combination is warranted, and future translation of such combination therapy into human beings is a possibility.

KW - Adenoviral vectors

KW - Bladder cancer

KW - Bone sialoprotein

KW - Cancer cell lines

KW - Gene therapy

UR - http://www.scopus.com/inward/record.url?scp=33745488231&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745488231&partnerID=8YFLogxK

U2 - 10.1016/j.urolonc.2005.11.028

DO - 10.1016/j.urolonc.2005.11.028

M3 - Review article

C2 - 16818192

AN - SCOPUS:33745488231

SN - 1078-1439

VL - 24

SP - 362

EP - 371

JO - Urologic Oncology: Seminars and Original Investigations

JF - Urologic Oncology: Seminars and Original Investigations

IS - 4 SPEC. ISS.

ER -

Conditionally replicating adenovirus-mediated gene therapy in bladder cancer: An orthotopic in vivo model

Abstract

Bibliographical note

Keywords

UN SDGs

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