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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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Effect of sex hormones on cell proliferation and cell death in vitro. A) Cell proliferation index measured for 4T1 cultures treated with P4 or E2, compared to controls. The data were obtained from three experiments. B) Appearance of 4T1 cultures treated with various doses of P4. A. control; B. E2; C. P4 15 ng/ML; D. P4 30 ng/ML; E, P4 60 ng/ml. Magnification of all images is 100×.Abbreviation: 4TI, mouse mammary cell lines.
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f5-ijn-5-221: Effect of sex hormones on cell proliferation and cell death in vitro. A) Cell proliferation index measured for 4T1 cultures treated with P4 or E2, compared to controls. The data were obtained from three experiments. B) Appearance of 4T1 cultures treated with various doses of P4. A. control; B. E2; C. P4 15 ng/ML; D. P4 30 ng/ML; E, P4 60 ng/ml. Magnification of all images is 100×.Abbreviation: 4TI, mouse mammary cell lines.

Mentions: We also investigated the effects of P4 on cell proliferation and cell death of 4T1 tumor cells in vitro. As shown in Figure 5A, a 30% reduction in cell proliferation is observed when 4T1 cells are treated with P4, as compared to vehicle-treated controls. In contrast, there is about a 40% increase in cell proliferation when the cells are treated by E2 as a positive control. We further evaluated the growth status of 4T1 cells after P4 treatment. The number of dead cells or detached cells increases dramatically when cells are treated with increasing doses of P4 for 24 hours (Figure 5B).


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)

Effect of sex hormones on cell proliferation and cell death in vitro. A) Cell proliferation index measured for 4T1 cultures treated with P4 or E2, compared to controls. The data were obtained from three experiments. B) Appearance of 4T1 cultures treated with various doses of P4. A. control; B. E2; C. P4 15 ng/ML; D. P4 30 ng/ML; E, P4 60 ng/ml. Magnification of all images is 100×.Abbreviation: 4TI, mouse mammary cell lines.
© Copyright Policy
Related In: Results  -  Collection

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

f5-ijn-5-221: Effect of sex hormones on cell proliferation and cell death in vitro. A) Cell proliferation index measured for 4T1 cultures treated with P4 or E2, compared to controls. The data were obtained from three experiments. B) Appearance of 4T1 cultures treated with various doses of P4. A. control; B. E2; C. P4 15 ng/ML; D. P4 30 ng/ML; E, P4 60 ng/ml. Magnification of all images is 100×.Abbreviation: 4TI, mouse mammary cell lines.
Mentions: We also investigated the effects of P4 on cell proliferation and cell death of 4T1 tumor cells in vitro. As shown in Figure 5A, a 30% reduction in cell proliferation is observed when 4T1 cells are treated with P4, as compared to vehicle-treated controls. In contrast, there is about a 40% increase in cell proliferation when the cells are treated by E2 as a positive control. We further evaluated the growth status of 4T1 cells after P4 treatment. The number of dead cells or detached cells increases dramatically when cells are treated with increasing doses of P4 for 24 hours (Figure 5B).

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