Limits...
Dimethylaminoparthenolide and gemcitabine: a survival study using a genetically engineered mouse model of pancreatic cancer.

Yip-Schneider MT, Wu H, Stantz K, Agaram N, Crooks PA, Schmidt CM - BMC Cancer (2013)

Bottom Line: Gemcitabine or the combination DMAPT/gemcitabine significantly increased median survival and decreased the incidence and multiplicity of pancreatic adenocarcinomas.The DMAPT/gemcitabine combination also significantly decreased tumor size and the incidence of metastasis to the liver.While gemcitabine treatment increased the levels of the inflammatory cytokines interleukin 1α (IL-1α), IL-1β, and IL-17 in mouse plasma, DMAPT and DMAPT/gemcitabine reduced the levels of the inflammatory cytokines IL-12p40, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 beta (MIP-1β), eotaxin, and tumor necrosis factor-alpha (TNF-α), all of which are NF-κB target genes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Indiana University School of Medicine, 980 W. Walnut St,, Building R3, Rm. 541C, Indianapolis, IN 46202, USA. myipschn@iupui.edu

ABSTRACT

Background: Pancreatic cancer remains one of the deadliest cancers due to lack of early detection and absence of effective treatments. Gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer, has limited clinical benefit. Treatment of pancreatic cancer cells with gemcitabine has been shown to induce the activity of the transcription factor nuclear factor-kappaB (NF-κB) which regulates the expression of genes involved in the inflammatory response and tumorigenesis. It has therefore been proposed that gemcitabine-induced NF-κB activation may result in chemoresistance. We hypothesize that NF-κB suppression by the novel inhibitor dimethylaminoparthenolide (DMAPT) may enhance the effect of gemcitabine in pancreatic cancer.

Methods: The efficacy of DMAPT and gemcitabine was evaluated in a chemoprevention trial using the mutant Kras and p53-expressing LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mouse model of pancreatic cancer. Mice were randomized to treatment groups (placebo, DMAPT [40 mg/kg/day], gemcitabine [50 mg/kg twice weekly], and the combination DMAPT/gemcitabine). Treatment was continued until mice showed signs of ill health at which time they were sacrificed. Plasma cytokine levels were determined using a Bio-Plex immunoassay. Statistical tests used included log-rank test, ANOVA with Dunnett's post-test, Student's t-test, and Fisher exact test.

Results: Gemcitabine or the combination DMAPT/gemcitabine significantly increased median survival and decreased the incidence and multiplicity of pancreatic adenocarcinomas. The DMAPT/gemcitabine combination also significantly decreased tumor size and the incidence of metastasis to the liver. No significant differences in the percentages of normal pancreatic ducts or premalignant pancreatic lesions were observed between the treatment groups. Pancreata in which no tumors formed were analyzed to determine the extent of pre-neoplasia; mostly normal ducts or low grade pancreatic lesions were observed, suggesting prevention of higher grade lesions in these animals. While gemcitabine treatment increased the levels of the inflammatory cytokines interleukin 1α (IL-1α), IL-1β, and IL-17 in mouse plasma, DMAPT and DMAPT/gemcitabine reduced the levels of the inflammatory cytokines IL-12p40, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 beta (MIP-1β), eotaxin, and tumor necrosis factor-alpha (TNF-α), all of which are NF-κB target genes.

Conclusion: In summary, these findings provide preclinical evidence supporting further evaluation of agents such as DMAPT and gemcitabine for the prevention and treatment of pancreatic cancer.

Show MeSH

Related in: MedlinePlus

The effect of treatment on median survival and tumor volume in LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mice. A) Median survival for each treatment group is shown in the Kaplan-Meier survival curve (placebo = 217.5 days; DMAPT = 233 days; Gem = 254.5 days; DMAPT/Gem = 255 days). * P < 0.05 for gemcitabine and DMAPT/gemcitabine vs. placebo by log-rank test. B) The tumor volume of individual pancreatic tumors within each treatment group is shown in the scatter plot. Note the difference in scale. Gem, gemcitabine. * P < 0.05 vs. placebo.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3672012&req=5

Figure 1: The effect of treatment on median survival and tumor volume in LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mice. A) Median survival for each treatment group is shown in the Kaplan-Meier survival curve (placebo = 217.5 days; DMAPT = 233 days; Gem = 254.5 days; DMAPT/Gem = 255 days). * P < 0.05 for gemcitabine and DMAPT/gemcitabine vs. placebo by log-rank test. B) The tumor volume of individual pancreatic tumors within each treatment group is shown in the scatter plot. Note the difference in scale. Gem, gemcitabine. * P < 0.05 vs. placebo.

Mentions: Treatment of the LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mice with either gemcitabine or the combination DMAPT/gemcitabine significantly increased the median survival time by more than 30 days compared to the placebo group (254.5 [P = 0.015] or 255 days [P = 0.018] vs. 217.5 days, respectively) (Figure 1A). The median survival for the DMAPT-treated mice (233 days), although longer, was not significantly different from the placebo group. No significant weight loss during the course of the study or other gross evidence of drug toxicity was noted in the treatment groups.


Dimethylaminoparthenolide and gemcitabine: a survival study using a genetically engineered mouse model of pancreatic cancer.

Yip-Schneider MT, Wu H, Stantz K, Agaram N, Crooks PA, Schmidt CM - BMC Cancer (2013)

The effect of treatment on median survival and tumor volume in LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mice. A) Median survival for each treatment group is shown in the Kaplan-Meier survival curve (placebo = 217.5 days; DMAPT = 233 days; Gem = 254.5 days; DMAPT/Gem = 255 days). * P < 0.05 for gemcitabine and DMAPT/gemcitabine vs. placebo by log-rank test. B) The tumor volume of individual pancreatic tumors within each treatment group is shown in the scatter plot. Note the difference in scale. Gem, gemcitabine. * P < 0.05 vs. placebo.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672012&req=5

Figure 1: The effect of treatment on median survival and tumor volume in LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mice. A) Median survival for each treatment group is shown in the Kaplan-Meier survival curve (placebo = 217.5 days; DMAPT = 233 days; Gem = 254.5 days; DMAPT/Gem = 255 days). * P < 0.05 for gemcitabine and DMAPT/gemcitabine vs. placebo by log-rank test. B) The tumor volume of individual pancreatic tumors within each treatment group is shown in the scatter plot. Note the difference in scale. Gem, gemcitabine. * P < 0.05 vs. placebo.
Mentions: Treatment of the LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mice with either gemcitabine or the combination DMAPT/gemcitabine significantly increased the median survival time by more than 30 days compared to the placebo group (254.5 [P = 0.015] or 255 days [P = 0.018] vs. 217.5 days, respectively) (Figure 1A). The median survival for the DMAPT-treated mice (233 days), although longer, was not significantly different from the placebo group. No significant weight loss during the course of the study or other gross evidence of drug toxicity was noted in the treatment groups.

Bottom Line: Gemcitabine or the combination DMAPT/gemcitabine significantly increased median survival and decreased the incidence and multiplicity of pancreatic adenocarcinomas.The DMAPT/gemcitabine combination also significantly decreased tumor size and the incidence of metastasis to the liver.While gemcitabine treatment increased the levels of the inflammatory cytokines interleukin 1α (IL-1α), IL-1β, and IL-17 in mouse plasma, DMAPT and DMAPT/gemcitabine reduced the levels of the inflammatory cytokines IL-12p40, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 beta (MIP-1β), eotaxin, and tumor necrosis factor-alpha (TNF-α), all of which are NF-κB target genes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Indiana University School of Medicine, 980 W. Walnut St,, Building R3, Rm. 541C, Indianapolis, IN 46202, USA. myipschn@iupui.edu

ABSTRACT

Background: Pancreatic cancer remains one of the deadliest cancers due to lack of early detection and absence of effective treatments. Gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer, has limited clinical benefit. Treatment of pancreatic cancer cells with gemcitabine has been shown to induce the activity of the transcription factor nuclear factor-kappaB (NF-κB) which regulates the expression of genes involved in the inflammatory response and tumorigenesis. It has therefore been proposed that gemcitabine-induced NF-κB activation may result in chemoresistance. We hypothesize that NF-κB suppression by the novel inhibitor dimethylaminoparthenolide (DMAPT) may enhance the effect of gemcitabine in pancreatic cancer.

Methods: The efficacy of DMAPT and gemcitabine was evaluated in a chemoprevention trial using the mutant Kras and p53-expressing LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mouse model of pancreatic cancer. Mice were randomized to treatment groups (placebo, DMAPT [40 mg/kg/day], gemcitabine [50 mg/kg twice weekly], and the combination DMAPT/gemcitabine). Treatment was continued until mice showed signs of ill health at which time they were sacrificed. Plasma cytokine levels were determined using a Bio-Plex immunoassay. Statistical tests used included log-rank test, ANOVA with Dunnett's post-test, Student's t-test, and Fisher exact test.

Results: Gemcitabine or the combination DMAPT/gemcitabine significantly increased median survival and decreased the incidence and multiplicity of pancreatic adenocarcinomas. The DMAPT/gemcitabine combination also significantly decreased tumor size and the incidence of metastasis to the liver. No significant differences in the percentages of normal pancreatic ducts or premalignant pancreatic lesions were observed between the treatment groups. Pancreata in which no tumors formed were analyzed to determine the extent of pre-neoplasia; mostly normal ducts or low grade pancreatic lesions were observed, suggesting prevention of higher grade lesions in these animals. While gemcitabine treatment increased the levels of the inflammatory cytokines interleukin 1α (IL-1α), IL-1β, and IL-17 in mouse plasma, DMAPT and DMAPT/gemcitabine reduced the levels of the inflammatory cytokines IL-12p40, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 beta (MIP-1β), eotaxin, and tumor necrosis factor-alpha (TNF-α), all of which are NF-κB target genes.

Conclusion: In summary, these findings provide preclinical evidence supporting further evaluation of agents such as DMAPT and gemcitabine for the prevention and treatment of pancreatic cancer.

Show MeSH
Related in: MedlinePlus