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Rich66 · 12-05-2009, 09:36 PM

http://www.ingentaconnect.com/conten...00001/00240475
An oral, brain barrier crossing, Anthracycline amenable to metronomic delivery:

Penetration of Idarubicin into Malignant Brain Tumor Tissue
Authors: Boogerd W.¹; Tjahja I.S.²; van de Sandt M.M.³; Beijnen J.H.⁴
Source: Journal of Neuro-Oncology, Volume 44, Number 1, August 1999 , pp. 65-69(5)
Publisher: Springer
Abstract:
Anthracyclines are effective in breast cancer and have in vitro cytotoxicity in glioma. In patients with glioma anthracyclines are not effective possibly because the hydrophilic drugs do not reach cytotoxic levels in tumor tissue. Idarubicin is more lipophilic than the other anthracyclines and is more cytotoxic in glioma cell lines. The uptake of idarubicin and its major metabolite idarubicinol in brain tumor tissue were measured in a patient with a brain metastasis from breast cancer and in 4 patients with malignant glioma after an oral dose of idarubicin (45 mg/m^2 in 1 patient; 25 mg/m^2 in 4 patients), given 15–24 h before brain tumor resection. The concentrations of idarubicin and of idarubicinol in tumor tissue exceeded the concurrent plasma concentrations as well as the peak plasma concentrations in all cases. The median tumor: concurrent plasma ratio of idarubicinol was 5.7 (range 1.7–18). The concentration of idarubicinol in the marginal zone between brain and tumor tissue was lower than in central tumor tissue, but was still higher than the plasma concentration in 2 of the 3 examined cases. Bone marrow suppression (platelets CTC grade 2, granulocytes CTC grade 4) occurred after a single dose of 45 ml/m^2. No toxicity was seen at a dose of 25 mg/m^2. These results, the in vitro activity of idarubicin in glioma, the convenience of oral administration, and its toxicity profile make clinical studies with idarubicin in malignant glioma, and perhaps also in brain metastases from breast cancer worthwhile.
1: Department of Neurology, Slotervaart Hospital, Amsterdam; Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands
2: Department of Neurosurgery, Slotervaart Hospital, Amsterdam 3: Department of Pathology, Slotervaart Hospital, Amsterdam
4: Department of Pharmacy, Slotervaart Hospital, Amsterdam; Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands

J Neurooncol. 2010 Jan 12. [Epub ahead of print]
Metronomic treatment of malignant glioma xenografts with irinotecan (CPT-11) inhibits angiogenesis and tumor growth.

Takano S, Kamiyama H, Mashiko R, Osuka S, Ishikawa E, Matsumura A.
Department of Neurosurgery, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba city, Ibaraki, 305-8575, Japan, shingo4@md.tsukuba.ac.jp.
Irinotecan (CPT-11) has shown emerging promise in the treatment of malignant gliomas. It is believed the mechanism of action of irinotecan is to sensitize glioma cells to the cytotoxic action of radiation therapy and alkylating agents. However, clinical trials using weekly or three-weekly doses of CPT-11 have demonstrated imaging responses in only 10-15% of patients. In this study, we evaluated another mechanism of action, angiosuppression by CPT-11 of ACNU-resistant gliomas, using a metronomic administration schedule. Two different types of treatment, (1) conventional and (2) metronomic, were applied to the subcutaneous U87 model. We found that metronomic administration of CPT-11 significantly inhibited malignant glioma growth by inhibiting angiogenesis; this treatment procedure reduced the number of tumor vessels and the area of hypoxic lesions and reduced expression of VEGF and HIF-1alpha, the most important angiogenic factors in gliomas. Metronomic treatment was superior to conventional treatment with regard to the severe systemic side effect of body weight loss. The growth inhibitory effect was very similar for both low and high doses of CPT-11. These angiosuppressive effects of CPT-11 show promise for another use of CPT-11 in metronomic and scheduled angiosuppressive chemotherapy with low dose and long-term administration for malignant gliomas without systemic side effects.

PMID: 20066473 [PubMed - as supplied by publisher]

Ai Zheng. 2007 Dec;26(12):1392-6.
[A new treatment protocol targeting tumor vasculature--- metronomic chemotherapy combined radiotherapy]

[Article in Chinese]
Qiu H, Wang GM.
Department of Radiotherapy, Huadong Hospital, Shanghai, 200040, PR China. qiuhao_limoges@188.com
Tumor growth and metastasis depend on its angiogenesis ability. The anti-angiogenic treatment is considered as a hopeful treatment for tumors. The anti-angiogenic efficacy of classic cytotoxic agents, such as cyclophosphomide, methotraxate, taxol, and so on, could be enhanced by changing the dose delivering schedule, naming "metronomic chemotherapy". Additionally, tumor vasculature and hypoxic status are important predictive factors for the efficacy of radiotherapy. Furthermore, the anti-angiogenic treatment can enhance the irradiation sensitivity of tumors. This review have summarized the anti-angiogenic mechanism of metronomic chemotherapy combined radiotherapy and the preliminary applications in clinic and proposed that the combination of radiotherapy and metronomic chemotherapy can overcome the hypoxia-related radioresistance and increase the efficacy of radiotherapy.

PMID: 18076810 [PubMed - indexed for MEDLINE]

Mo Med. 2009 Nov-Dec;106(6):428-31.
Brain metastases secondary to breast cancer: treatment with surgical resection and stereotactic radiosurgery.

Tolentino PJ.
Brain and NeuroSpine Clinic of Missouri, LLC, Cape Girardeau, MO, USA. ptolentino@brainandneurospine.com
Intracerebral metastases are a serious complication for a significant proportion of cancer patients. Successful management may involve multiple treatments including surgical resection, whole-brain radiotherapy (WBRT), and stereotactic radiosurgery (SRS). We report the successful treatment of a solitary brain metastasis using a combination of surgical resection and SRS at Southeast Missouri Hospital, a community hospital that serves a primarily rural population.

PMID: 20063515 [PubMed - in process]

12-05-2009, 09:36 PM	#5
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Brain mets http://www.ingentaconnect.com/conten...00001/00240475 An oral, brain barrier crossing, Anthracycline amenable to metronomic delivery: Penetration of Idarubicin into Malignant Brain Tumor Tissue Authors: Boogerd W.¹; Tjahja I.S.²; van de Sandt M.M.³; Beijnen J.H.⁴ Source: Journal of Neuro-Oncology, Volume 44, Number 1, August 1999 , pp. 65-69(5) Publisher: Springer Abstract: Anthracyclines are effective in breast cancer and have in vitro cytotoxicity in glioma. In patients with glioma anthracyclines are not effective possibly because the hydrophilic drugs do not reach cytotoxic levels in tumor tissue. Idarubicin is more lipophilic than the other anthracyclines and is more cytotoxic in glioma cell lines. The uptake of idarubicin and its major metabolite idarubicinol in brain tumor tissue were measured in a patient with a brain metastasis from breast cancer and in 4 patients with malignant glioma after an oral dose of idarubicin (45 mg/m^2 in 1 patient; 25 mg/m^2 in 4 patients), given 15–24 h before brain tumor resection. The concentrations of idarubicin and of idarubicinol in tumor tissue exceeded the concurrent plasma concentrations as well as the peak plasma concentrations in all cases. The median tumor: concurrent plasma ratio of idarubicinol was 5.7 (range 1.7–18). The concentration of idarubicinol in the marginal zone between brain and tumor tissue was lower than in central tumor tissue, but was still higher than the plasma concentration in 2 of the 3 examined cases. Bone marrow suppression (platelets CTC grade 2, granulocytes CTC grade 4) occurred after a single dose of 45 ml/m^2. No toxicity was seen at a dose of 25 mg/m^2. These results, the in vitro activity of idarubicin in glioma, the convenience of oral administration, and its toxicity profile make clinical studies with idarubicin in malignant glioma, and perhaps also in brain metastases from breast cancer worthwhile. 1: Department of Neurology, Slotervaart Hospital, Amsterdam; Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands 2: Department of Neurosurgery, Slotervaart Hospital, Amsterdam 3: Department of Pathology, Slotervaart Hospital, Amsterdam 4: Department of Pharmacy, Slotervaart Hospital, Amsterdam; Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands J Neurooncol. 2010 Jan 12. [Epub ahead of print] Metronomic treatment of malignant glioma xenografts with irinotecan (CPT-11) inhibits angiogenesis and tumor growth. Takano S, Kamiyama H, Mashiko R, Osuka S, Ishikawa E, Matsumura A. Department of Neurosurgery, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba city, Ibaraki, 305-8575, Japan, shingo4@md.tsukuba.ac.jp. Irinotecan (CPT-11) has shown emerging promise in the treatment of malignant gliomas. It is believed the mechanism of action of irinotecan is to sensitize glioma cells to the cytotoxic action of radiation therapy and alkylating agents. However, clinical trials using weekly or three-weekly doses of CPT-11 have demonstrated imaging responses in only 10-15% of patients. In this study, we evaluated another mechanism of action, angiosuppression by CPT-11 of ACNU-resistant gliomas, using a metronomic administration schedule. Two different types of treatment, (1) conventional and (2) metronomic, were applied to the subcutaneous U87 model. We found that metronomic administration of CPT-11 significantly inhibited malignant glioma growth by inhibiting angiogenesis; this treatment procedure reduced the number of tumor vessels and the area of hypoxic lesions and reduced expression of VEGF and HIF-1alpha, the most important angiogenic factors in gliomas. Metronomic treatment was superior to conventional treatment with regard to the severe systemic side effect of body weight loss. The growth inhibitory effect was very similar for both low and high doses of CPT-11. These angiosuppressive effects of CPT-11 show promise for another use of CPT-11 in metronomic and scheduled angiosuppressive chemotherapy with low dose and long-term administration for malignant gliomas without systemic side effects. PMID: 20066473 [PubMed - as supplied by publisher] Ai Zheng. 2007 Dec;26(12):1392-6. [A new treatment protocol targeting tumor vasculature--- metronomic chemotherapy combined radiotherapy] [Article in Chinese] Qiu H, Wang GM. Department of Radiotherapy, Huadong Hospital, Shanghai, 200040, PR China. qiuhao_limoges@188.com Tumor growth and metastasis depend on its angiogenesis ability. The anti-angiogenic treatment is considered as a hopeful treatment for tumors. The anti-angiogenic efficacy of classic cytotoxic agents, such as cyclophosphomide, methotraxate, taxol, and so on, could be enhanced by changing the dose delivering schedule, naming "metronomic chemotherapy". Additionally, tumor vasculature and hypoxic status are important predictive factors for the efficacy of radiotherapy. Furthermore, the anti-angiogenic treatment can enhance the irradiation sensitivity of tumors. This review have summarized the anti-angiogenic mechanism of metronomic chemotherapy combined radiotherapy and the preliminary applications in clinic and proposed that the combination of radiotherapy and metronomic chemotherapy can overcome the hypoxia-related radioresistance and increase the efficacy of radiotherapy. PMID: 18076810 [PubMed - indexed for MEDLINE] Mo Med. 2009 Nov-Dec;106(6):428-31. Brain metastases secondary to breast cancer: treatment with surgical resection and stereotactic radiosurgery. Tolentino PJ. Brain and NeuroSpine Clinic of Missouri, LLC, Cape Girardeau, MO, USA. ptolentino@brainandneurospine.com Intracerebral metastases are a serious complication for a significant proportion of cancer patients. Successful management may involve multiple treatments including surgical resection, whole-brain radiotherapy (WBRT), and stereotactic radiosurgery (SRS). We report the successful treatment of a solitary brain metastasis using a combination of surgical resection and SRS at Southeast Missouri Hospital, a community hospital that serves a primarily rural population. PMID: 20063515 [PubMed - in process] __________________ Mom's treatment history (link)