Derivation of MPR and TRAMP models of prostate cancer and prostate cancer metastasis for evaluation of therapeutic strategies

Voeks, Dale J.; Martiniello‐Wilks, Rosetta; Russell, Pamela J.

doi:10.1016/s1078-1439(01)00180-6

Cited by 25 publications

(33 citation statements)

References 12 publications

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“…This antitumor activity was evident despite being challenged with a high dose (2.5 Â 10 5 cells) of highly aggressive parental RM1 cells (22). Although this was more evident in the GDEPT + cytokine -treated mice, the long-term effects of treatment would need to be exhaustively analyzed in another series of experiments using larger cohorts to yield statistical significance.…”

Section: Discussionmentioning

confidence: 99%

“…RM1 cells implanted into the prostate or tail vein of C57BL/6 mice induce tumor formation and experimental lung metastasis, respectively, in an aggressive and reproducible manner (22). Intraprostatic injections were done with 5 Â 10 3 RM1CDUPRT or RM1 cells in the subcapsular region of the prostate surgically, whereas 2.5 Â 10 5 RM1 cells were injected i.v.…”

Section: Methodsmentioning

confidence: 99%

“…That both are required for significant expression of the Th1 phenotype was also confirmed by studies of mice deficient in IL-12 and IL-18, which display remarkably reduced IFN-g production, impaired NK cell activity, and defective Th1 cell responses (21). We report here the effects of this combination treatment on local and remote tumor growth and mouse survival in an orthotopic model of murine prostate cancer (22). The growth kinetics (cell proliferation and apoptosis), tumor vasculature, and immune cell infiltration in tumors were also assessed.…”

mentioning

confidence: 99%

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Cytosine Deaminase-Uracil Phosphoribosyltransferase and Interleukin (IL)-12 and IL-18: A Multimodal Anticancer Interface Marked by Specific Modulation in Serum Cytokines

Khatri

Husaini²,

et al. 2009

Clinical Cancer Research

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Purpose: To test the effects of a new combination, cytosine deaminase (CD) + uracil phosphoribosyltransferase (UPRT)^mediated gene-directed enzyme prodrug therapy (GDEPT) with interleukin (IL)-12 and IL-18, on (a) growth of murine prostate and remote tumor deposits, (b) mouse survival, and (c) T helper (Th) 1/Th2 serum cytokine balance with a special focus to assess correlation with tumor burden/survival. Experimental Design: Efficacy of intraprostatic administration of adenovirally delivered murine IL-12 and IL-18 against orthotopic RM1 tumors and lung pseudometastases was assessed in C57BL/6 mice. At necropsy, tumor growth, lung colony counts, effects on immune cell infiltration, vasculature, apoptosis, and proliferation were estimated. Next, CDUPRT-GDEPT + cytokines were tested at suboptimal doses in mice with RM1CDUPRT prostate tumors/RM1 lung deposits and analyzed as above. Effects on mouse survival were also assessed. Host immune responses to different treatments were assessed by monitoring 11serum cytokines using Luminex technology. Results: Our data show that IL-12 and IL-18, when combined with CDUPRT-GDEPT, caused significant reduction in local RM1 tumors and lung colonies with enhanced long-term survival versus individual treatments. A dramatic enhancement of tumor infiltration by a wider repertoire of immune cells and disruption of vasculature implied the combination to be more immunostimulatory and antiangiogenic. Remarkably, lowering of serum IL-4 and monocyte chemoattractant protein-1 (MCP-1) was consistently associated with lower tumor burden (local and systemic), and this, rather than an increase inTh1cytokines, better predicted treatment efficacy. In addition, mouse survival correlated with substantially higher cytokine (Th1/Th2) levels after treatment. Conclusion: Locoregional application of CDUPRT-GDEPTand IL-12/IL-18 was effective against local and systemic prostate cancer and improved survival. Monitoring serum levels of IL-4 and MCP-1may accurately reflect tumor burden and, hence, host response to therapy.Heterogeneity of clinical prostate cancer has culminated in inadequacy of single-treatment regimens and inefficient patient management. An urgent need has emerged for (a) new combination regimens that can be given into the primary tumor with systemic effects and without toxicities and (b) design of preclinical screening to generate clinically relevant data.Immunostimulatory strategies have the potential to combat cancer and generate long-term anticancer effects. However, poorly immunogenic tumors and immunocompromised patients pose a challenge. The in situ amplification of cytotoxicity via local and distant bystander effects by locally delivered gene-directed enzyme prodrug therapies (GDEPT) is shown to be inflammatory [T cells, macrophages, and natural killer (NK) cells], and several studies support the concept that further enhancement is possible using cytokines (1). This was first shown when IL-2 combined with thymidine kinasebased GDEPT (HSV-tk) was found to be more potent aga...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Cytosine Deaminase-Uracil Phosphoribosyltransferase and Interleukin (IL)-12 and IL-18: A Multimodal Anticancer Interface Marked by Specific Modulation in Serum Cytokines

Khatri

Husaini²,

et al. 2009

Clinical Cancer Research

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“…While direct injection to bone is not a true metastasis model and precludes insight into earlier steps of the metastatic process, information regarding late steps in the metastatic process, such as tumor growth/invasion within bone and tumor:bone stromal interactions, can be obtained. In the current study, tail vein injections were not examined since RM1 cell injection to the tail vein has previously been shown to yield massive lung metastases resulting in high mortality rates shortly following injection [17].…”

Section: Discussionmentioning

confidence: 99%

Intraosseous injection of RM1 murine prostate cancer cells promotes rapid osteolysis and periosteal bone deposition

McCabe

Madajka

Vasanji

et al. 2008

Clin Exp Metastasis

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The molecular mechanisms associated with prostate cancer (PCa) progression within bone remain a topic of intense investigation. With the availability of transgenic mouse strains, a model of PCa for use in immune competent/transgenic mice would be highly beneficial. This study was designed to explore the utility of RM1 mouse PCa cells in investigations of tumor:bone interactions. The efficacies of several implantation techniques were examined for reliably producing intra-bone RM1 tumor growth and bone lesion formation in immune competent mice. Longitudinal monitoring of bone remodeling and lesion phenotypes was conducted by microcomputed tomography (μCT) and histological analyses. Our results indicate that direct intrabone injections of RM1 cells are necessary for tumor growth within bone and direct implantation promotes the rapid development of osteolytic bone lesions with periosteal bone deposition post-cortical breach. In vitro, RM1 cells promote the proliferation of osteoblast (MC3T3-E1) and osteoclast (Raw264.7) progenitors in a dose dependent manner. Conditioned culture media from RM1 cells appears to promote earlier expression of genes/ proteins associated with osteoblastic differentiation. While clearly stimulating osteoclast function in vivo, RM1 cells had little effect on differentiation and tartate resistant acid phosphatase (TRAP) expression by Raw264.7 cells. These data, coupled with in vivo μCT images, indicate the ability of RM1 cells to induce mixed, yet predominentally osteolytic, responses in bone and illustrate the potential of RM1 cells as a model of investigating prostate tumor:stroma interactions in immune competent/transgenic mice on a C57BL/6 background.

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“…S2). Orthotopic (intraprostatic; Iprost) RMI cells (5 Â 10 3 ) were surgically implanted in the subcapsular region of the prostate of C57BL/6 male mice as described (21). On day 5, Ad/CMV/PNP (10 9 pfus/cell) was injected into the prostate tumors, followed by i.v.…”

Section: Evaluation Of Synergy Between Docetaxel and Gdept In C57bl/6mentioning

confidence: 99%

Molecular Chemotherapy and Chemotherapy: A New Front against Late-Stage Hormone-Refractory Prostate Cancer

Singh

Joshi

Russell

et al. 2011

Clinical Cancer Research

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Purpose: Stemming from its inherent heterogeneity, single-agent treatments are essentially ineffective against castration-resistant prostate cancer (CRPC). Thus, clinically relevant regimens that harness different modalities to maximize treatment efficacy without increasing cumulative toxicities are urgently needed. Based on this rationale, we investigated whether a novel combination of purine nucleoside phosphorylase–mediated, gene-directed enzyme-prodrug therapy (PNP-GDEPT) with docetaxel against CRPC has superior efficacy in comparison with individual treatments. Methods: The in vitro cell growth inhibition in differentially treated murine and human CRPC cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The local and systemic effects of docetaxel and/or PNP-GDEPT were tested in both immunodeficient and immunocompetent mice against human and murine CRPC tumors, respectively. Subsequently, immunohistochemical analyses and an evaluation of serum cytokine and serum toxicity profiles were conducted to characterize the differential host responses to treatment. Results: The combined use of PNP-GDEPT and docetaxel led to strong synergistic cell killing in vitro. Compared with the individual modalities, a combination of the 2 led to a marked reduction in “local and distant” tumor growth in vivo, and importantly, with lowered doses and without additional toxicities. Immunomodulation was indicated by enhanced immune cell infiltration and altered serum cytokine levels. Furthermore, a lowering of T-helper type 2 cytokines, MCP-1, interleukin (IL)-4, IL-6, and IL-10 marked lower tumor burden and enhanced treatment efficacy. Conclusion: PNP-GDEPT and docetaxel are a potent combination against CRPC in immunocompetent and immunodeficient settings; these outcomes have implications of translational potential for improved treatment and management of CRPC patients. Clin Cancer Res; 17(12); 4006–18. ©2011 AACR.

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Derivation of MPR and TRAMP models of prostate cancer and prostate cancer metastasis for evaluation of therapeutic strategies

Cited by 25 publications

References 12 publications

Cytosine Deaminase-Uracil Phosphoribosyltransferase and Interleukin (IL)-12 and IL-18: A Multimodal Anticancer Interface Marked by Specific Modulation in Serum Cytokines

Cytosine Deaminase-Uracil Phosphoribosyltransferase and Interleukin (IL)-12 and IL-18: A Multimodal Anticancer Interface Marked by Specific Modulation in Serum Cytokines

Intraosseous injection of RM1 murine prostate cancer cells promotes rapid osteolysis and periosteal bone deposition

Molecular Chemotherapy and Chemotherapy: A New Front against Late-Stage Hormone-Refractory Prostate Cancer

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