Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of metastatic brain tumor from breast cancer

Afroz Shareef Mohammad, Chris E. Adkins, Neal Shah, Rawaa Aljammal, Jessica I.G. Griffith, Rachel M. Tallman, Katherine L. Jarrell, Paul R. Lockman

Research output: Contribution to journalArticle

Abstract

Background: Brain tumor vasculature can be significantly compromised and leakier than that of normal brain blood vessels. Little is known if there are vascular permeability alterations in the brain adjacent to tumor (BAT). Changes in BAT permeability may also lead to increased drug permeation in the BAT, which may exert toxicity on cells of the central nervous system. Herein, we studied permeation changes in BAT using quantitative fluorescent microscopy and autoradiography, while the effect of chemotherapy within the BAT region was determined by staining for activated astrocytes. Methods: Human metastatic breast cancer cells (MDA-MB-231Br) were injected into left ventricle of female NuNu mice. Metastases were allowed to grow for 28 days, after which animals were injected fluorescent tracers Texas Red (625 Da) or Texas Red dextran (3 kDa) or a chemotherapeutic agent 14 C-paclitaxel. The accumulation of tracers and 14 C-paclitaxel in BAT were determined by using quantitative fluorescent microscopy and autoradiography respectively. The effect of chemotherapy in BAT was determined by staining for activated astrocytes. Results: The mean permeability of texas Red (625 Da) within BAT region increased 1.0 to 2.5-fold when compared to normal brain, whereas, Texas Red dextran (3 kDa) demonstrated mean permeability increase ranging from 1.0 to 1.8-fold compared to normal brain. The K in values in the BAT for both Texas Red (625 Da) and Texas Red dextran (3 kDa) were found to be 4.32 ± 0.2 × 10 5 mL/s/g and 1.6 ± 1.4 × 10 5 mL/s/g respectively and found to be significantly higher than the normal brain. We also found that there is significant increase in accumulation of 14 C-Paclitaxel in BAT compared to the normal brain. We also observed animals treated with chemotherapy (paclitaxel (10 mg/kg), erubilin (1.5 mg/kg) and docetaxel (10 mg/kg)) showed activated astrocytes in BAT. Conclusions: Our data showed increased permeation of fluorescent tracers and 14 C-paclitaxel in the BAT. This increased permeation lead to elevated levels of activated astrocytes in BAT region in the animals treated with chemotherapy.

Original languageEnglish (US)
Article number1225
JournalBMC Cancer
Volume18
Issue number1
DOIs
StatePublished - Dec 7 2018
Externally publishedYes

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Brain Neoplasms
Permeability
Theoretical Models
Breast Neoplasms
Drug Therapy
Brain
Neoplasms
Paclitaxel
Astrocytes
Dextrans
docetaxel
Autoradiography
Microscopy
Staining and Labeling
Capillary Permeability
Heart Ventricles
Blood Vessels
Texas red

Keywords

  • Astrocytosis
  • Autoradiography
  • Brain metastases
  • Chemotherapy
  • Fluorescent microscopy

PubMed: MeSH publication types

  • Journal Article

Cite this

Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of metastatic brain tumor from breast cancer. / Mohammad, Afroz Shareef; Adkins, Chris E.; Shah, Neal; Aljammal, Rawaa; Griffith, Jessica I.G.; Tallman, Rachel M.; Jarrell, Katherine L.; Lockman, Paul R.

In: BMC Cancer, Vol. 18, No. 1, 1225, 07.12.2018.

Research output: Contribution to journalArticle

Mohammad, Afroz Shareef ; Adkins, Chris E. ; Shah, Neal ; Aljammal, Rawaa ; Griffith, Jessica I.G. ; Tallman, Rachel M. ; Jarrell, Katherine L. ; Lockman, Paul R. / Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of metastatic brain tumor from breast cancer. In: BMC Cancer. 2018 ; Vol. 18, No. 1.
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abstract = "Background: Brain tumor vasculature can be significantly compromised and leakier than that of normal brain blood vessels. Little is known if there are vascular permeability alterations in the brain adjacent to tumor (BAT). Changes in BAT permeability may also lead to increased drug permeation in the BAT, which may exert toxicity on cells of the central nervous system. Herein, we studied permeation changes in BAT using quantitative fluorescent microscopy and autoradiography, while the effect of chemotherapy within the BAT region was determined by staining for activated astrocytes. Methods: Human metastatic breast cancer cells (MDA-MB-231Br) were injected into left ventricle of female NuNu mice. Metastases were allowed to grow for 28 days, after which animals were injected fluorescent tracers Texas Red (625 Da) or Texas Red dextran (3 kDa) or a chemotherapeutic agent 14 C-paclitaxel. The accumulation of tracers and 14 C-paclitaxel in BAT were determined by using quantitative fluorescent microscopy and autoradiography respectively. The effect of chemotherapy in BAT was determined by staining for activated astrocytes. Results: The mean permeability of texas Red (625 Da) within BAT region increased 1.0 to 2.5-fold when compared to normal brain, whereas, Texas Red dextran (3 kDa) demonstrated mean permeability increase ranging from 1.0 to 1.8-fold compared to normal brain. The K in values in the BAT for both Texas Red (625 Da) and Texas Red dextran (3 kDa) were found to be 4.32 ± 0.2 × 10 5 mL/s/g and 1.6 ± 1.4 × 10 5 mL/s/g respectively and found to be significantly higher than the normal brain. We also found that there is significant increase in accumulation of 14 C-Paclitaxel in BAT compared to the normal brain. We also observed animals treated with chemotherapy (paclitaxel (10 mg/kg), erubilin (1.5 mg/kg) and docetaxel (10 mg/kg)) showed activated astrocytes in BAT. Conclusions: Our data showed increased permeation of fluorescent tracers and 14 C-paclitaxel in the BAT. This increased permeation lead to elevated levels of activated astrocytes in BAT region in the animals treated with chemotherapy.",
keywords = "Astrocytosis, Autoradiography, Brain metastases, Chemotherapy, Fluorescent microscopy",
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T1 - Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of metastatic brain tumor from breast cancer

AU - Mohammad, Afroz Shareef

AU - Adkins, Chris E.

AU - Shah, Neal

AU - Aljammal, Rawaa

AU - Griffith, Jessica I.G.

AU - Tallman, Rachel M.

AU - Jarrell, Katherine L.

AU - Lockman, Paul R.

PY - 2018/12/7

Y1 - 2018/12/7

N2 - Background: Brain tumor vasculature can be significantly compromised and leakier than that of normal brain blood vessels. Little is known if there are vascular permeability alterations in the brain adjacent to tumor (BAT). Changes in BAT permeability may also lead to increased drug permeation in the BAT, which may exert toxicity on cells of the central nervous system. Herein, we studied permeation changes in BAT using quantitative fluorescent microscopy and autoradiography, while the effect of chemotherapy within the BAT region was determined by staining for activated astrocytes. Methods: Human metastatic breast cancer cells (MDA-MB-231Br) were injected into left ventricle of female NuNu mice. Metastases were allowed to grow for 28 days, after which animals were injected fluorescent tracers Texas Red (625 Da) or Texas Red dextran (3 kDa) or a chemotherapeutic agent 14 C-paclitaxel. The accumulation of tracers and 14 C-paclitaxel in BAT were determined by using quantitative fluorescent microscopy and autoradiography respectively. The effect of chemotherapy in BAT was determined by staining for activated astrocytes. Results: The mean permeability of texas Red (625 Da) within BAT region increased 1.0 to 2.5-fold when compared to normal brain, whereas, Texas Red dextran (3 kDa) demonstrated mean permeability increase ranging from 1.0 to 1.8-fold compared to normal brain. The K in values in the BAT for both Texas Red (625 Da) and Texas Red dextran (3 kDa) were found to be 4.32 ± 0.2 × 10 5 mL/s/g and 1.6 ± 1.4 × 10 5 mL/s/g respectively and found to be significantly higher than the normal brain. We also found that there is significant increase in accumulation of 14 C-Paclitaxel in BAT compared to the normal brain. We also observed animals treated with chemotherapy (paclitaxel (10 mg/kg), erubilin (1.5 mg/kg) and docetaxel (10 mg/kg)) showed activated astrocytes in BAT. Conclusions: Our data showed increased permeation of fluorescent tracers and 14 C-paclitaxel in the BAT. This increased permeation lead to elevated levels of activated astrocytes in BAT region in the animals treated with chemotherapy.

AB - Background: Brain tumor vasculature can be significantly compromised and leakier than that of normal brain blood vessels. Little is known if there are vascular permeability alterations in the brain adjacent to tumor (BAT). Changes in BAT permeability may also lead to increased drug permeation in the BAT, which may exert toxicity on cells of the central nervous system. Herein, we studied permeation changes in BAT using quantitative fluorescent microscopy and autoradiography, while the effect of chemotherapy within the BAT region was determined by staining for activated astrocytes. Methods: Human metastatic breast cancer cells (MDA-MB-231Br) were injected into left ventricle of female NuNu mice. Metastases were allowed to grow for 28 days, after which animals were injected fluorescent tracers Texas Red (625 Da) or Texas Red dextran (3 kDa) or a chemotherapeutic agent 14 C-paclitaxel. The accumulation of tracers and 14 C-paclitaxel in BAT were determined by using quantitative fluorescent microscopy and autoradiography respectively. The effect of chemotherapy in BAT was determined by staining for activated astrocytes. Results: The mean permeability of texas Red (625 Da) within BAT region increased 1.0 to 2.5-fold when compared to normal brain, whereas, Texas Red dextran (3 kDa) demonstrated mean permeability increase ranging from 1.0 to 1.8-fold compared to normal brain. The K in values in the BAT for both Texas Red (625 Da) and Texas Red dextran (3 kDa) were found to be 4.32 ± 0.2 × 10 5 mL/s/g and 1.6 ± 1.4 × 10 5 mL/s/g respectively and found to be significantly higher than the normal brain. We also found that there is significant increase in accumulation of 14 C-Paclitaxel in BAT compared to the normal brain. We also observed animals treated with chemotherapy (paclitaxel (10 mg/kg), erubilin (1.5 mg/kg) and docetaxel (10 mg/kg)) showed activated astrocytes in BAT. Conclusions: Our data showed increased permeation of fluorescent tracers and 14 C-paclitaxel in the BAT. This increased permeation lead to elevated levels of activated astrocytes in BAT region in the animals treated with chemotherapy.

KW - Astrocytosis

KW - Autoradiography

KW - Brain metastases

KW - Chemotherapy

KW - Fluorescent microscopy

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