Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection

Schroers, Roland; Cm, Davis; Hj, Wagner; Sy, Chen

doi:10.1038/sj.gt.3301711

Cited by 38 publications

(33 citation statements)

References 47 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…21 It was also reported that neutralizing antibody to SDF-1 decreased the proliferation of bone-homing metastatic prostate cancer cells. 14 Most recently, Zeelenberg et al 25 reported that blocking the surface expression of CXCR4 with an ''intrakine'', developed in our laboratory, 23,24 greatly reduced the ability of CT26 colon cancer cells to metastasize to the liver and lungs. This effect was not attributed to the inhibition of tumor cell invasion, but rather to the impairment of outgrowth of micrometastases.…”

Section: Cxcr4 Knockdown Abrogates Breast Tumor Growth N Lapteva Et Almentioning

confidence: 97%

CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo

et al. 2004

View full text Add to dashboard Cite

Breast cancer cells express the chemokine receptor CXCR4 and frequently metastasize to organs with an abundant source of the CXCR4 ligand, stromal cell-derived factor 1 (SDF-1). The chemokine receptor CXCR4 plays an active role in the metastasis of breast cancer. Here, we show that a small interfering RNA (siRNA) against CXCR4 effectively downregulates CXCR4 expression in human MDA-MB-231 breast cancer cells, leading to significant decrease in breast cancer cell invasion and adhesion. It was further found that tumor cells lacking CXCR4 expression proliferated at a much slower rate than control cells in vitro. Surprisingly, tumor cells lacking CXCR4 expression failed to grow in SCID mice in repeated experiments, providing the first direct evidence for an essential role of CXCR4 in breast cancer growth in vivo. This finding suggests an expanded role for the CXCR4 molecule in tumor cell growth in vivo, in addition to its role in breast cancer metastasis. This study implies the CXCR4 molecule as a potential target to control breast tumor growth as well as metastasis. Cancer Gene Therapy ( Keywords: CXCR4; breast cancer; tumor growth; invasion; adhesion C hemokines are small proteins that stimulate and attract leukocytes to sites of inflammation. 1 CXCR4, the receptor for SDF-1/CXCL12, plays an important role in lymphocyte trafficking. 2,3 Breast and other cancer cells express the chemokine receptor CXCR4, and frequently metastasize to organs that are an abundant source of its ligand, SDF-1. 4,5 Recent reports indicate that CXCR4 is intimately involved in the metastasis of several different types of cancer, including prostate cancer, 6 renal cancer, 7 neuroblastoma, 8 ovarian cancer, 9 breast cancer, 4 and melanoma. 10 Complete disruption of the CXCR4 chemokine receptor gene is embryologically lethal in mice, 11,12 impeding direct study of CXCR4-mediated tumor progression and metastasis. Current approaches to study CXCR4-mediated tumor metastasis are based on the functional blocking of CXCR4 on tumor cell surfaces with CXCR4 antagonists 13 and CXCR4 neutralizing antibodies. 14 The results of such studies using different cancer cell lines show that inhibition of CXCR4 reduces the frequency of metastasis 13,14 suggesting that the receptor is essential for tumor-cell dissemination and invasion of tissues.We chose to use small interfering RNA (siRNA) as a means to constitutively inhibit CXCR4 expression in tumor cells, thus facilitating a more vigorous assessment of the role of CXCR4 in tumor metastasis. Unexpectedly, we found that stable transduction of MDA-MB-231 breast cancer cells with siRNA targeting CXCR4 completely abrogated tumor growth in SCID mice. The results of this study suggested that, in addition to its established role in tumor metastasis, CXCR4 expression contributes importantly to tumor growth in vivo, implicating this chemokine receptor as a potentially valuable therapeutic target to control both breast tumor growth and metastasis. Materials and methods Generation of DNA constructs and stably transform...

show abstract

Section: Cxcr4 Knockdown Abrogates Breast Tumor Growth N Lapteva Et Almentioning

confidence: 97%

CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Intratumoral injection of adenoviral vector encoding macrophage-derived chemokine (MDC, CCL22) resulted in marked tumor regression of Lewis lung carcinoma through strong chemoattracting activity of dendritic cells (DC), NK cells, and T lymphocytes [16]. Gene transfer of another CC chemokine, RANTES (CCL5) [17], or of the C chemokine lymphotactin (XCL1) [18] also exhibited strong antitumor activity in solid tumor models. These results suggested that chemokines could mediate innate and adaptive antitumor immune response by recruiting monocytes, DC, NK, and T lymphocytes into tumor sites.…”

Section: Introductionmentioning

confidence: 99%

“…Some chemokines induce angiogenesis and thus promote tumor growth and metastasis [14,15]. However, tumor suppression by chemokine gene transfer into tumor cells has been demonstrated in animal models [16][17][18]. Intratumoral injection of adenoviral vector encoding macrophage-derived chemokine (MDC, CCL22) resulted in marked tumor regression of Lewis lung carcinoma through strong chemoattracting activity of dendritic cells (DC), NK cells, and T lymphocytes [16].…”

Section: Introductionmentioning

confidence: 99%

Antitumor immune response by CX3CL1 fractalkine gene transfer depends on both NK and T cells

et al. 2005

View full text Add to dashboard Cite

The CX3C chemokine fractalkine (CX3CL1) exists as both a membrane-bound form promoting firm cell-cell adhesion and a soluble form chemoattracting leukocytes expressing its receptor CX3CR1. When adenoviral vector expressing mouse fractalkine (AdFKN) was transduced to the tumor cells, fractalkine was expressed as both membrane-bound form on the tumor cells and soluble form in the supernatant in vitro. Intratumoral injection of AdFKN (1Â10 9 PFU/tumor) into C26 and B16F10 tumors resulted in marked reduction of tumor growth compared to control (C26: 86.5%, p<0.001; B16F10: 85.5%, p<0.001). Histological examination of tumor tissues revealed abundant infiltration of NK cells, dendritic cells, and CD8 + T lymphocytes 3 and/or 6 days after treatment with AdFKN. Splenocytes from mice treated by AdFKN developed tumor-specific cytotoxic T cells, and thereby protected from rechallenging with parental tumor cells. Antitumor effects by AdFKN were completely abrogated in both NK celldepleted mice and CD8 -/-mice, and partially blocked in CD4 -/-mice. These data indicated that fractalkine mediates antitumor effects by both NK cell-dependent and T cell-dependent mechanisms. This study suggests that fractalkine can be a suitable candidate for immunogene therapy of cancer because fractalkine induces both innate and adaptive immunity.

show abstract

“…This mutant protein is one of the most potent inhibitors of HIV replication. Intracellular antibodies and intrakines have also proven to be very potent inhibitors of HIV replication [42][43][44][45][46] . These proteins work by binding to viral or cellular target proteins, most often resulting in targeting of the proteins to the proteasome for degradation.…”

Section: Protein-based Inhibitorsmentioning

confidence: 99%

Genetic therapies against HIV

2007

View full text Add to dashboard Cite

Highly active antiretroviral therapy prolongs the life of HIV-infected individuals, but it requires lifelong treatment and results in cumulative toxicities and viral-escape mutants. Gene therapy offers the promise of preventing progressive HIV infection by sustained interference with viral replication in the absence of chronic chemotherapy. Gene-targeting strategies are being developed with RNA-based agents, such as ribozymes, antisense, RNA aptamers and small interfering RNA, and protein-based agents, such as the mutant HIV Rev protein M10, fusion inhibitors and zincfinger nucleases. Recent advances in T-cell-based strategies include gene-modified HIV-resistant T cells, lentiviral gene delivery, CD8 + T cells, T bodies and engineered T-cell receptors. HIVresistant hematopoietic stem cells have the potential to protect all cell types susceptible to HIV infection. The emergence of viral resistance can be addressed by therapies that use combinations of genetic agents and that inhibit both viral and host targets. Many of these strategies are being tested in ongoing and planned clinical trials.Controlling HIV infection continues to be a major challenge in both underdeveloped and developed nations. Although the drug cocktails used in highly active antiretroviral therapy (HAART) have markedly changed the profile of progression to AIDS in HIV-infected individuals, they are not without significant problems and drawbacks. Pharmacokinetic differences between individuals result in many drug-related toxicities, leading to problems of nonadherence, although the increase in side effects is due in part to the improved lifespan brought by the very success of antiretroviral therapies. There is a need for personalized dosing regimens and combinations and for continued therapeutic monitoring of the drugs themselves. Drug failures for those on HAART continue to occur as a consequence of viral resistance and other complications arising from a lifelong regimen of chemotherapy. In addition, treatment guidelines traditionally have not recommended initiating therapy in the Correspondence should be addressed to J.J.R. (jrossi@coh.org).

show abstract

Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection

Cited by 38 publications

References 47 publications

CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo

CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo

Antitumor immune response by CX3CL1 fractalkine gene transfer depends on both NK and T cells

Genetic therapies against HIV

Contact Info

Product

Resources

About