Thalidomide suppressed the growth of 4T1 cells into solid tumors in Balb/c mice in a combination therapy with the oncolytic fusogenic HSV-1 OncdSyn

Israyelyan, Anna; Shannon, E. J.; Baghian, Abolghasem; Kearney, Michael T.; Kousoulas, Konstantin G.

doi:10.1007/s00280-009-0987-8

Cited by 16 publications

(8 citation statements)

References 42 publications

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“…Although our oncolytic HSV1 can reduce the primary 4T1 tumor volume effectively, which is consistent with the previous reports [27,59,60,65,66], and decrease the frequency of ALDH br cells compared with chemotherapy, it also has its own limitations, including physical barriers such as the extracellular matrix, which restrict the initial distribution and subsequent spread of viruses in the tumor mass when the oncolytic virus is directly injected into the tumor, and anti-HSV1 immunity, which can limit virus replication when locally or systematically given repeatedly [67,68]. These limitations may be overcome by combination of viral and chemotherapies.…”

Section: Discussionsupporting

confidence: 93%

Doxorubicin-enriched, ALDHbr mouse breast cancer stem cells are treatable to oncolytic herpes simplex virus type 1

et al. 2012

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BackgroundThe primary objective of this study was to test whether oncolytic herpes simplex virus type 1 (HSV1) could eradicate chemoresistant cancer stem cells (CSCs).MethodsThe fluorescent aldefluor reagent-based technique was used to identify and isolate ALDHbr cells as CSCs from the 4T1 murine breast cancer cell line. The presence of ALDHbr 4T1 cells was also examined in 4T1 breast cancer transplanted in immune-competent syngeneic mice.ResultsCompared with ALDHlo cells, ALDHbr cells had a markedly higher ability to form tumor spheres in vitro and a higher tumorigenic potential in vivo. ALDHbr cells also exhibited increased doxorubicin resistance in vitro, which correlated with a selective increase in the percentage of ALDHbr cells after doxorubicin treatment and an increased expression of P-glycoprotein (P-gp), a known chemoresistance factor. In contrast, oncolytic HSV1 was able to kill ALDHbr cells in vitro and even more markedly in vivo. Furthermore, in in vivo studies, systemic administration of doxorubicin followed by intratumoral injection of oncolytic HSV1 resulted in much more significant suppression of tumor growth with increased median survival period compared with each treatment given alone (p<0.05). Though more CD8+ T lymphocytes were induced by oncolytic HSV1, no significant specific T cell response against CSCs was detected in vivo.ConclusionsThese results suggested that the use of oncolytic HSV1 following doxorubicin treatment may help eradicate residual chemoresistant CSCs in vivo.

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Section: Discussionsupporting

confidence: 93%

Doxorubicin-enriched, ALDHbr mouse breast cancer stem cells are treatable to oncolytic herpes simplex virus type 1

et al. 2012

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“…They suggest that Thal acts as an activator of the immune response. In our two studies using this model, Thal retarded the growth of tumors, but it did not significantly limit the ability of established primary tumors to increase in size, (1) nor did it inhibit developing tumors from increasing in size. Indirect evidence in this model suggests that Thal did not act primarily as an inhibitor of angiogenesis, or as an inhibitor of proliferation of the tumor cells, or as an inhibitor of adhesion molecules on the cells that may have been necessary for tumor formation and growth.…”

Section: Discussionmentioning

confidence: 90%

“…(1) In that study we injected 4T1 cells into Balb/c mice and after the tumors had become palpable, the mice were fed a diet containing Thal at 0.03% weight/weight for 4 days. In the control group of mice, fed with meal, 19 of 22 (86%) had tumors that increased in volume > 2.0 mm 3 , whereas only 12 of 20 (60%) fed with meal + Thal had tumors that increased in volume > 2.0 mm 3 .…”

Section: Introductionmentioning

confidence: 99%

Thalidomide delayed the ability of 4T1 cells to amass into tumors in Balb/c mice

Israyelyan¹,

Sandoval²,

Baghian³

et al. 2011

Immunopharmacology and Immunotoxicology

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Thalidomide (Thal) can suppress the growth of established, as well as explanted tumors in mice. We wanted to determine if it could suppress the ability of tumor cells to assemble and establish a primary tumor at the injection site. Using the mouse 4T1 mammary tumor model, we fed Thal to mice for 4 days, then injected 10(5) 4T1 cells into the interscapular region of Balb/c mice. After 20 days on treatment with Thal, all seven control mice, fed with meal had tumors ranging from 3 to 93 mm(3) (median 20). Two of the eight mice fed with meal + Thal had no tumors, and the remaining mice had tumors ranging from 2 to 22 mm(3) (median 5). The median volume of the tumors in the control group was significantly more than that of mice treated with Thal (p = 0.03, Mann-Whitney test). In vitro treatment of the 4T1cells with Thal did not inhibit their ability to proliferate, to adhere to plastic, or to bind to Concanavalin-A. Thal caused a marked reduction in the ability of the 4T1 cells to assemble into palpable tumors.

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“…It was investigated in conjunction with OncdSyn in a murine syngeneic mammary carcinoma model. Either thalidomide or OncdSyn alone was effective in reducing tumor burden, but the combination resulted in an additional significant benefit [80]. The mechanism of action is unclear, but thalidomide did not inhibit tumor or endothelial cell proliferation, and the combination did not alter the cytokine profile of splenocytes isolated from treated mice [80].…”

Section: Combination With Other Pharmacological Agentsmentioning

confidence: 99%

Oncolytic Herpes Simplex Virus Vectors and Chemotherapy: Are Combinatorial Strategies More Effective for Cancer?

et al. 2010

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Despite aggressive treatments, including chemotherapy and radiotherapy, cancers often recur owing to resistance to conventional therapies. Oncolytic viruses such as oncolytic herpes simplex virus (oHSV) represent an exciting biological approach to cancer therapy. A range of viral mutations has been engineered into HSV to engender oncolytic activity. While oHSV as a single agent has been tested in a number of cancer clinical trials, preclinical studies have demonstrated enhanced efficacy when it is combined with cytotoxic anticancer drugs. Among the strategies that will be discussed in this article are combinations with standard-of-care chemotherapeutics, expression of prodrug-activating enzymes to enhance chemotherapy and small-molecule inhibitors. The combination of oHSV and chemotherapy can achieve much more efficient cancer cell killing than either single agent alone, often through synergistic interactions. This can be clinically important not just for improving efficacy but also for permitting lower and less toxic chemotherapeutic doses. The viral mutations in an oHSV vector often determine the favorability of its interactions with chemotherapy, just as different cancer cells, due to genetic alterations, vary in their response to chemotherapy. As chemotherapeutics are often the standard of care, combining them with an investigational new drug, such as oHSV, is clinically easier than combining multiple novel agents. As has become clear for most cancer therapies, multimodal treatments are usually more effective. In this article, we will discuss the recent progress of these combinatorial strategies between virotherapy and chemotherapy and future directions.

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Thalidomide suppressed the growth of 4T1 cells into solid tumors in Balb/c mice in a combination therapy with the oncolytic fusogenic HSV-1 OncdSyn

Abstract: Thalidomide alone delayed tumor growth, but the combination of thalidomide with OncdSyn appeared to produce the best results.

Cited by 16 publications

References 42 publications

Doxorubicin-enriched, ALDHbr mouse breast cancer stem cells are treatable to oncolytic herpes simplex virus type 1

Doxorubicin-enriched, ALDHbr mouse breast cancer stem cells are treatable to oncolytic herpes simplex virus type 1

Thalidomide delayed the ability of 4T1 cells to amass into tumors in Balb/c mice

Oncolytic Herpes Simplex Virus Vectors and Chemotherapy: Are Combinatorial Strategies More Effective for Cancer?

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