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Optimizing the time of Doxil injection to increase the drug retention in transplanted murine mammary tumors.

You S, Zuo L, Li W - Int J Nanomedicine (2010)

Bottom Line: It has been proposed that the liposomal formulated doxorubicin (ie, Doxil), given at the menstrual/estrous stage with the predicted highest tumor vascular permeability, allows significantly increased drug retention in the breast tumor.By using 4T1 cells cultured in vitro, we showed that progesterone (P4) significantly inhibited cell proliferation and the production of six tumor-derived cytokines, eg, sTNF-RI, CXCL-16, GM-CSF, MIP-1alpha, MIP-1gamma, and Flt3-L.Some of these factors have been shown to be vascular modulators in diverse tissues.

View Article: PubMed Central - PubMed

Affiliation: Experimental Cancer Therapeutic Laboratory and Histopathology Core, Atlanta Research and Educational Foundation (151F), Atlanta VA Medical Center, Decatur, GA, USA. shaojin.you@va.gov

ABSTRACT
Sex hormonal milieus during the female fertility cycle modulate the tumor vascular permeability of breast cancer. It has been proposed that the liposomal formulated doxorubicin (ie, Doxil), given at the menstrual/estrous stage with the predicted highest tumor vascular permeability, allows significantly increased drug retention in the breast tumor. In the current study, syngeneic murine 4T1 mammary tumors were established on the backs of female BALB/c mice and Doxil was administered at particular mouse estrous cycle stages. The results indicated that Doxil administration during certain times in the mouse estrous cycle was crucial for drug retention in 4T1 tumor tissues. Significantly higher drug concentrations were detected in the tumor tissues when Doxil was administered during the diestrus stage, as compared to when the drug injection was given at all other estrous stages. Our study also showed that the tumor-bearing mice exhibited nearly normal rhythmicity of the estrous cycle post drug injection, indicating the feasibility of continual injection of Doxil at the same estrous cycle stage. By using 4T1 cells cultured in vitro, we showed that progesterone (P4) significantly inhibited cell proliferation and the production of six tumor-derived cytokines, eg, sTNF-RI, CXCL-16, GM-CSF, MIP-1alpha, MIP-1gamma, and Flt3-L. Some of these factors have been shown to be vascular modulators in diverse tissues. In this report, we demonstrated that the concentration of P4 in the plasma and/or estrous cycle stage of 4T1 tumor-bearing mice can be used to select the best time for administrating the liposomal anticancer drugs.

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P4 treatment and cytokine expression in vitro. Scanned signal intensity of the hybridized protein array spots from a cytokine microarray assay of conditioned medium from 4T1 mouse mammary cell cultures treated with progesterone for 24 hours. Each bar represents the average values from two hybridized spots of duplicate assays with subtraction of the baseline reading (baseline reading value = 100).
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f4-ijn-5-221: P4 treatment and cytokine expression in vitro. Scanned signal intensity of the hybridized protein array spots from a cytokine microarray assay of conditioned medium from 4T1 mouse mammary cell cultures treated with progesterone for 24 hours. Each bar represents the average values from two hybridized spots of duplicate assays with subtraction of the baseline reading (baseline reading value = 100).

Mentions: Sex hormones are rhythmically changing during the mouse estrous cycle. Plasma levels of estradiol (E2) fluctuate between 3.1 and 10.5 pg/mL during mouse estrous cycle,12 while plasma progesterone (P4) levels alternate between 8 and 60 ng/mL. Diestrus in mice corresponds to the lowest plasma P4 concentration.13 To determine the potential effects of the dynamic P4 levels on tumor derived cytokine secretion, the conditioned medium was harvested from 4T1 cell culture dishes and submitted to protein expression profiling analysis using a mouse cytokine antibody microarray. As shown in Figure 4, sTNF-RI, CXCL-16, GM-CSF, MIP-3α, MIP-1γ, and Flt3-L are decreased dramatically (P < 0.05). Surprisingly, vascular endothelial growth receptor and basic fibroblast growth factor do not change as compared to vehicle-treated controls (data not shown).


Optimizing the time of Doxil injection to increase the drug retention in transplanted murine mammary tumors.

You S, Zuo L, Li W - Int J Nanomedicine (2010)

P4 treatment and cytokine expression in vitro. Scanned signal intensity of the hybridized protein array spots from a cytokine microarray assay of conditioned medium from 4T1 mouse mammary cell cultures treated with progesterone for 24 hours. Each bar represents the average values from two hybridized spots of duplicate assays with subtraction of the baseline reading (baseline reading value = 100).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2865017&req=5

f4-ijn-5-221: P4 treatment and cytokine expression in vitro. Scanned signal intensity of the hybridized protein array spots from a cytokine microarray assay of conditioned medium from 4T1 mouse mammary cell cultures treated with progesterone for 24 hours. Each bar represents the average values from two hybridized spots of duplicate assays with subtraction of the baseline reading (baseline reading value = 100).
Mentions: Sex hormones are rhythmically changing during the mouse estrous cycle. Plasma levels of estradiol (E2) fluctuate between 3.1 and 10.5 pg/mL during mouse estrous cycle,12 while plasma progesterone (P4) levels alternate between 8 and 60 ng/mL. Diestrus in mice corresponds to the lowest plasma P4 concentration.13 To determine the potential effects of the dynamic P4 levels on tumor derived cytokine secretion, the conditioned medium was harvested from 4T1 cell culture dishes and submitted to protein expression profiling analysis using a mouse cytokine antibody microarray. As shown in Figure 4, sTNF-RI, CXCL-16, GM-CSF, MIP-3α, MIP-1γ, and Flt3-L are decreased dramatically (P < 0.05). Surprisingly, vascular endothelial growth receptor and basic fibroblast growth factor do not change as compared to vehicle-treated controls (data not shown).

Bottom Line: It has been proposed that the liposomal formulated doxorubicin (ie, Doxil), given at the menstrual/estrous stage with the predicted highest tumor vascular permeability, allows significantly increased drug retention in the breast tumor.By using 4T1 cells cultured in vitro, we showed that progesterone (P4) significantly inhibited cell proliferation and the production of six tumor-derived cytokines, eg, sTNF-RI, CXCL-16, GM-CSF, MIP-1alpha, MIP-1gamma, and Flt3-L.Some of these factors have been shown to be vascular modulators in diverse tissues.

View Article: PubMed Central - PubMed

Affiliation: Experimental Cancer Therapeutic Laboratory and Histopathology Core, Atlanta Research and Educational Foundation (151F), Atlanta VA Medical Center, Decatur, GA, USA. shaojin.you@va.gov

ABSTRACT
Sex hormonal milieus during the female fertility cycle modulate the tumor vascular permeability of breast cancer. It has been proposed that the liposomal formulated doxorubicin (ie, Doxil), given at the menstrual/estrous stage with the predicted highest tumor vascular permeability, allows significantly increased drug retention in the breast tumor. In the current study, syngeneic murine 4T1 mammary tumors were established on the backs of female BALB/c mice and Doxil was administered at particular mouse estrous cycle stages. The results indicated that Doxil administration during certain times in the mouse estrous cycle was crucial for drug retention in 4T1 tumor tissues. Significantly higher drug concentrations were detected in the tumor tissues when Doxil was administered during the diestrus stage, as compared to when the drug injection was given at all other estrous stages. Our study also showed that the tumor-bearing mice exhibited nearly normal rhythmicity of the estrous cycle post drug injection, indicating the feasibility of continual injection of Doxil at the same estrous cycle stage. By using 4T1 cells cultured in vitro, we showed that progesterone (P4) significantly inhibited cell proliferation and the production of six tumor-derived cytokines, eg, sTNF-RI, CXCL-16, GM-CSF, MIP-1alpha, MIP-1gamma, and Flt3-L. Some of these factors have been shown to be vascular modulators in diverse tissues. In this report, we demonstrated that the concentration of P4 in the plasma and/or estrous cycle stage of 4T1 tumor-bearing mice can be used to select the best time for administrating the liposomal anticancer drugs.

Show MeSH
Related in: MedlinePlus