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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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The time of Doxil administration during mouse estrous cycle and its effects on drug retention in 4T1 tumors. A) The Dox concentrations in 4T1 tumors when Doxil is injected during diestrus stage or other estrous stages. B) The dynamic changes of serum progesterone and estrogen levels during the estrous cycle. The concentrations of P4 and E2 in mice were previously published.13 The best time for Doxil injection is indicated by the black arrow and bar. The worst times for Doxil injection are indicated by small triangles and dotted bars.
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f1-ijn-5-221: The time of Doxil administration during mouse estrous cycle and its effects on drug retention in 4T1 tumors. A) The Dox concentrations in 4T1 tumors when Doxil is injected during diestrus stage or other estrous stages. B) The dynamic changes of serum progesterone and estrogen levels during the estrous cycle. The concentrations of P4 and E2 in mice were previously published.13 The best time for Doxil injection is indicated by the black arrow and bar. The worst times for Doxil injection are indicated by small triangles and dotted bars.

Mentions: To test our hypothesis, we conducted two animal experiments. For each experiment, subcutaneous murine 4T1 mammary tumors were established on the backs of female BALB/c mice. In the first group of mice, Doxil was injected when the 4T1 tumors were ∼1,500 mm3 and the tumor-bearing mice were sacrificed 24 hours later. Tumor tissues were harvested and Dox concentration within each tumor was measured. As shown in Figure 1A, Dox concentrations in the 4T1 tumors were significantly higher (7.74 μ equivalents/mL, n = 3) when the drug was injected during the diestrus stage, as compared to those tumors when the drug was injected in all other estrous stages (1.38 μ equivalents/mL, n = 6; P = 0.01). These data suggest that the diestrus stage may represent the best time for Doxil injection in 4T1 tumor-bearing mice (Figure 1B).


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)

The time of Doxil administration during mouse estrous cycle and its effects on drug retention in 4T1 tumors. A) The Dox concentrations in 4T1 tumors when Doxil is injected during diestrus stage or other estrous stages. B) The dynamic changes of serum progesterone and estrogen levels during the estrous cycle. The concentrations of P4 and E2 in mice were previously published.13 The best time for Doxil injection is indicated by the black arrow and bar. The worst times for Doxil injection are indicated by small triangles and dotted bars.
© Copyright Policy
Related In: Results  -  Collection

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

f1-ijn-5-221: The time of Doxil administration during mouse estrous cycle and its effects on drug retention in 4T1 tumors. A) The Dox concentrations in 4T1 tumors when Doxil is injected during diestrus stage or other estrous stages. B) The dynamic changes of serum progesterone and estrogen levels during the estrous cycle. The concentrations of P4 and E2 in mice were previously published.13 The best time for Doxil injection is indicated by the black arrow and bar. The worst times for Doxil injection are indicated by small triangles and dotted bars.
Mentions: To test our hypothesis, we conducted two animal experiments. For each experiment, subcutaneous murine 4T1 mammary tumors were established on the backs of female BALB/c mice. In the first group of mice, Doxil was injected when the 4T1 tumors were ∼1,500 mm3 and the tumor-bearing mice were sacrificed 24 hours later. Tumor tissues were harvested and Dox concentration within each tumor was measured. As shown in Figure 1A, Dox concentrations in the 4T1 tumors were significantly higher (7.74 μ equivalents/mL, n = 3) when the drug was injected during the diestrus stage, as compared to those tumors when the drug was injected in all other estrous stages (1.38 μ equivalents/mL, n = 6; P = 0.01). These data suggest that the diestrus stage may represent the best time for Doxil injection in 4T1 tumor-bearing mice (Figure 1B).

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