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Static magnetic fields impair angiogenesis and growth of solid tumors in vivo
Strelczyk D, Eichhorn ME, Luedemann S, Brix G, Dellian M, Berghaus A, Strieth S.
Walter-Brendel-Center for Experimental Medicine (WBex), Campus Grosshadern, University of Munich (LMU), Munich, Germany.
Exposure to static magnetic fields (SMFs) results in a reduced blood
flow in tumor vessels as well as in activation and adherence of
platelets. Whether this phenomenon may have a significant functional
impact on tumors has not been investigated as yet. The aim of our study
was to evaluate the effects of prolonged exposure to SMFs on tumor
angiogenesis and growth. Experiments were performed in dorsal skinfold
chamber preparations of Syrian Golden hamsters bearing syngenic A-Mel-3
melanomas. On 3 d following tumor cell implantation one group of animals
was immobilized and exposed to a SMF of 586 mT for three h. Control
animals were immobilized for the same duration without SMF exposure.
Using in vivo-fluorescence microscopy the field effects on tumor
angiogenesis and microcirculation were analyzed for seven days. Tumor
growth was assessed by repeated planimetry of the tumor area during the
observation period. Exposure to SMFs resulted in a significant
retardation of tumor growth ( approximately 30%). Furthermore,
histological analysis showed an increased peri- and intratumoral edema
in tumors exposed to SMFs. Analysis of microcirculatory parameters
revealed a significant reduction of functional vessel density, vessel
diameters and red blood cell velocity in tumors after exposure to SMFs
compared to control tumors. These changes reflect retarded vessel
maturation by antiangiogenesis. The increased edema after SMF exposure
indicates an increased tumor microvessel leakiness possibly enhancing
drug-uptake. Hence, SMF therapy appears as a promising new anticancer
strategy-as an inhibitor of tumor growth and angiogenesis and as a
potential sensitizer to chemotherapy.
Strelczyk D, Eichhorn ME, Luedemann S, Brix G, Dellian M, Berghaus A,
Strieth S (September 2009). "Static magnetic fields impair angiogenesis
and growth of solid tumors in vivo." Cancer Biology and Therapy. 8 (18):1756-62. PMID: 19633422
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Static magnetic fields induce blood flow decrease and platelet adherence in tumor microvessels.
Strieth S, Strelczyk D, Eichhorn ME, Dellian M, Luedemann S, Griebel J, Bellemann M, Berghaus A, Brix G.
Department of Otorhinolaryngology, University of Munich (LMU), Marchioninistr. 15, Munich 81377 Germany.
Red blood cell flow in capillaries is reduced during exposure to
strong static magnetic fields (SMFs). Intratumoral microcirculation is
characterized by tortuous microvessels with chaotic architecture and by
irregular, sluggish blood flow with unstable rheology. It was the aim of
this study to analyze SMF exposure effects on tumor microcirculation
with regard to interactions of corpuscular blood components with tumor
microvessel walls.
In vivo fluorescence microscopy was performed in A-Mel-3 tumors
growing in dorsal skinfold chamber preparations of Syrian Golden
hamsters. SMFs with varying field strength (< 600 mT) were generated
by changing the distance between a strong NdFeB rod magnet and the
tissue region of interest.
Short-time exposure above a magnetic flux density of about 150 mT
resulted in a significant reduction of red blood cell velocity (vRBC)
and segmental blood flow in tumor microvessels. At the maximum strength
of 587 mT, a reversible reduction of vRBC (approximately 40%) and of
functional vessel densitiy (approximately 15%) was observed.
Prolongation of the exposure time from 1 min to up to 3 h resulted in
comparable reductions. Microvessel diameters and leukocyte-endothelial
cell interactions remained unaffected by SMF exposure. However, in
contrast to tumor-free striated muscle controls, exposure at the maximum
flux density induced a significant increase in platelet-endothelial
cell adherence in a time-dependent manner that was reversible after
reducing SMF strength.
These reversible changes may have implications for functional
measurements of tumor microcirculation by MRI and new therapeutic
strategies using strong SMFs.
Strieth S, Strelczyk D, Eichhorn ME, Dellian M, Luedemann S, Griebel
J, Bellemann M, Berghaus A, Brix G (June 2008). "Static magnetic fields
induce blood flow decrease and platelet adherence in tumor
microvessels." Cancer Biology & Therapy. 7(6):814-9. PMID: 18340115
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Effect of magnetic fields on human and rodent cancer cell survival.
Tata, D., Vanhoutten, N., Brook, C., &TrItton T.
In a laboratory study, several rodent and human cancer cell
types were exposed to permanent magnetic fields for one hour to
determine what percent of the cells would survive compared to unexposed
cells. The permanent magnetic field was extremely strong (11.6 Tesla =
116,000 gauss) and was generated by sophisticated equipment. Some of the
surviving cell fractions included 25% for human breast carcinoma, 40%
for human ovarian carcinoma, and 4% for human mouth carcinoma.
Non-Invasive permanent magnetic field modality induces lethal effects on
several rodent and human cancers.
In Vitro. Proceedings of the American Association for Cancer Research, 1994; 35, 386.
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Use of artificial magnetic field for rehabilitation of children with malignant tumors.
Kiselev AV, Grushina TI.
N.N. Blokhin Center for Oncology Research, Russian Academy of Medical Sciences, Moscow.
Local complications of standard intravenous injections for
chemotherapy and due to error of administration were compared in 400
patients (200 of them children) and general wound pathologies described.
Treatment for wounds included two modalities: standard medication and
alternating or pulsating magnetic field. Magnetic therapy proved highly
effective: wound healing was 3-3.5 times faster while duration of
treatment--2-3 times shorter than in standard procedure.
Clinically-verified partial adhesion-related intestinal obstruction was
eliminated by magnetic procedure in 18 children after combined treatment
for lymphosarcoma involving the ileum.
Vopr Onkol. 2000;46(4):469-72.
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Antitumor effect of new local hyperthermia using dextran magnetite complex in hamster tongue carcinoma.
Wada S, Tazawa K, Furuta I, Nagae H.
Department oqf Dentistry and Oral Surgery, Faculty of
Medicine, Toyama Medical and Pharmaceutical University, Sugitani,
Toyama, Japan. swada-tym@umin.ac.jp
OBJECTIVE: This study was performed to clarify the usefulness of Dextran magnetite (DM) for the oral cancer hyperthermia.
METHODS: Tumors were induced in golden hamster tongue by
9,10-dimethyl 1-1,2-benzanthracene (DMBA) application. DM suspension was
locally injected into the tumor-bearing tongue and tongues were heated
up to 43.0-45.0 degrees C, by AC magnetic field of 500 kHz.
RESULTS: The average time taken for the temperature to rise
to 43.0 degrees C or above was 162 s (n = 17) at the margin of the tumor
and 420 s (n = 17) at the center of the tumor. According to the tumor
volume, the time required for an increase in the central temperature of
tumor to 43.0 degrees C tended to be prolonged. Both temperatures could
be maintained at approximately 43.0-45.0 degrees C for 30 min. The
inhibition of the growth of tongue carcinoma in the four-time heating
group was significantly greater than in the control group (P < 0.01).
Moreover, the survival rate was significantly higher in the heated
groups than in the control group (P < 0.01). Histological examination
revealed a brown uniform DM accumulation at the stroma in the margin of
the tumors. Many of tumor cells disappeared at the site adjacent to
this accumulation.
CONCLUSION: These results strongly suggest the usefulness of
this local hyperthermic system in the oral region that is accessible to
this treatment.
Oral Dis. 2003 Jul;9(4):218-23.
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Phase I clinical study of a static magnetic field combined
with anti-neoplastic chemotherapy in the treatment of human malignancy:
initial safety and toxicity data.
Salvatore JR, Harrington J, Kummet T.
Division of Hematology-Oncology, Carl T Hayden VA Medical Center, Phoenix, Arizona 85012, USA. joseph.salvatore@med.va.gov
We have completed the lowest level of exposure in a Phase I
study, designed to establish the safety and toxicity of the combination
of a static magnetic field (SMF) and antineoplastic chemotherapy in
patients with advanced malignancy. The SMF application is carefully
controlled by applying the magnet to the patient only in our clinic
during chemotherapy administration. No increase in the severity of
chemotherapy toxicity as measured by white blood cell count and platelet
count was seen in the participants exposed to SMF compared to the
historical control subjects. These data have permitted the next group of
subjects to be treated at the next dose level. Published 2003
Wiley-Liss, Inc.
Bioelectromagnetics. 2003 Oct;24(7):524-7.
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Targeting therapy of magnetic doxorubicin liposome in nude mice bearing colon cancer.
Zhou PH, Yao LQ, Qin XY, Shen XZ, Liu YS, Lu WY, Yao M.
Zhongshan Hospital, Fudan University, Shanghai 200032, China.
OBJECTIVE: To investigate the effect of magnetic doxorubicin
liposome (MDL) in the targeting treatment of nude mice bearing colon
cancer.
METHODS: Human colon cancer line LoVo cells were implanted
hypodermically into nude mouse. Two weeks after the mouse was killed and
the tumor was taken out and cut into small pieces to be retransplanted
into nude mice so as to establish an experimental model. MDL was
prepared by reverse-phase evaporation method. The particle size and
structure of MDL were evaluated. Eighteen nude mice with colon cancer
were divided into 3 groups of 3 mice: free DOX group, MDL (-) group (no
magnetic field was added to the tumor surface), and MDL (+) group
(magnetic field with the strength of 4 500 G was added). DOX of the
dosage of 5 mg/kg was injected through the caudal vein in these 3
groups. Then the mice were killed 30 minutes after. Fluorescence
spectrophotometry was used to examine the concentrations of DOX in the
tissues and plasma. Another 36 nude mice with colon cancer were divided
into 6 groups of 6 mice: normal saline group (as controls), DOX group,
blank liposome group, magnetic liposome group, MDL (-) group
(non-magnetic alloy was implanted into the tumor), and MDL (+) group
(rare earth magnet was implanted into the tumor). The body weight,
longest diameter of tumor, and short diameter vertical to the longest
diameter were calculated regularly. The mice were killed 11 days after.
The tumors were taken out to undergo staining and light microscopy. Flow
cytometry was used to examine the apoptosis of tumor cells.
RESULTS: The particle size of MDL was 230 nm and the magnetic
particles (Fe(3)O(4)) were evenly distributed within the liposome. The
DOX concentration in tumor tissue of the MDL (+) group was remarkably
higher than those of the DOX and MDL (-) groups (both P < 0.05). The
DOX concentration in heart and kidney of the DOX group were higher than
those of the other 2 groups, and the plasma DOX concentrations of the
DOX group was significantly lower than those of the other groups (all P
< 0.05). The growth speed of tumor in the MDL (+) group was
significantly lower, and the tumor weight was significantly less than in
other groups.
CONCLUSION: Magnetic doxorubicin liposome, as a carrier of
anticancer drug, has a good targeting function toward the magnetite and
has a significant anticancer effect.
Zhonghua Yi Xue Za Zhi. 2003 Dec;83(23):2073-6.
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Heat shock protein 70 gene therapy combined with hyperthermia using magnetic nanoparticles.
Ito A, Matsuoka F, Honda H, Kobayashi T.
Department of Biotechnology, School of Engineering, Nagoya University, Nagoya 464-8603, Japan.
Heat shock proteins (HSPs) are recognized as significant
participants in immune reactions. We previously reported that expression
of HSP70 in response to hyperthermia, produced using our original
magnetite cationic liposomes (MCLs), induces antitumor immunity. In the
present study, we examine whether the antitumor immunity induced by
hyperthermia is enhanced by hsp70 gene transfer. A human hsp70 gene
mediated by cationic liposomes was injected into a B16 melanoma nodule
in C57BL/6 mice in situ. At 24 hours after the injection of the hsp70
gene, MCLs were injected into melanoma nodules in C57BL/6 mice, which
were subjected to an alternating magnetic field for 30 minutes. The
temperature at the tumor reached 43 degrees C and was maintained by
controlling the magnetic field intensity. The combined treatment
strongly arrested tumor growth over a 30-day period, and complete
regression of tumors was observed in 30% (3/10) of mice. Systemic
antitumor immunity was induced in the cured mice. This study
demonstrates that this novel therapeutic strategy combining the use of
hsp70 gene therapy and hyperthermia using MCLs may be applicable to
patients with advanced malignancies.
Cancer Gene Ther. 2003 Dec; 10(12): 918-25.
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Investigation on T_c tuned nano particles of magnetic oxides for hyperthermia applications.
Giri J, Ray A, Dasgupta S, Datta D, Bahadur D.
Department of Metallurgical Engineering and Materials Science, Indian Institute of Technology, Powai, Mumbai-400076, India.
Superparamagnetic as well as fine ferrimagnetic particles
such as Fe_{3}O_{4}, have been extensively used in magnetic field
induced localized hyperthermia for the treatment of cancer. The magnetic
materials with Curie temperature (T_c) between 42 and 50 degrees C,
with sufficient biocompatibility are the best candidates for effective
treatment such that during therapy it acts as in vivo temperature
control switch and thus over heating could be avoided. Ultrafine
particles of substituted ferrite Co_{1-a}Zn_{a}Fe_{2}O_{4} and
substituted yttrium-iron garnet Y_{3}Fe_{5-x}Al_{x}O_{12} have been
prepared through microwave refluxing and citrate-gel route respectively.
Single-phase compounds were obtained with particle size below 100 nm.
In order to make these magnetic nano particles biocompatible, we have
attempted to coat these above said composition by alumina. The coating
of alumina was done by hydrolysis method. The coating of hydrous
aluminium oxide has been done over the magnetic particles by aging the
preformed solid particles in the solution of aluminium sulfate and
formamide at elevated temperatures. In vitro study is carried out to
verify the innocuousness of coated materials towards cells. In vitro
biocompatibility study has been carried out by cell culture method for a
period of three days using human WBC cell lines. Study of cell counts
and SEM images indicates the cells viability/growth. The in vitro
experiments show that the coated materials are biocompatible.
Biomed Mater Eng. 2003;13(4):387-399.
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Antitumor effects of combined therapy of recombinant heat
shock protein 70 and hyperthermia using magnetic nanoparticles in an
experimental subcutaneous murine melanoma.
Ito A, Matsuoka F, Honda H, Kobayashi T.
Department of Biotechnology, School of Engineering, Nagoya University, Nagoya 464-8603, Japan.
Heat shock proteins (HSPs) are recognized as significant
participants in cancer immunity. We previously reported that HSP70
expression following hyperthermia using magnetic nanoparticles induces
antitumor immunity. In the present study, we examine whether the
antitumor immunity induced by hyperthermia is enhanced by administration
of recombinant HSP70 protein into the tumor in situ. Hyperthermia was
conducted using our original magnetite cationic liposomes (MCLs), which
have a positive surface charge and generate heat in an alternating
magnetic field (AMF) due to hysteresis loss. MCLs and recombinant mouse
HSP70 (rmHSP70) were injected into melanoma nodules in C57BL/6 mice,
which were subjected to AMF for 30 min. Temperature within the tumor
reached 43 degrees C and was maintained by controlling the magnetic
field intensity. The combined treatment strongly inhibited tumor growth
over a 30-day period and complete regression of tumors was observed in
20% (2/10) of mice. It was also found that systemic antitumor immunity
was induced in the cured mice. This study suggests that novel combined
therapy using exogenous HSP70 and hyperthermia has great potential in
cancer treatment.
Cancer Immunol Immunother. 2004 Jan;53(1):26-32. Epub 2003 Oct 09.
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Significant differences in the effects of magnetic field
exposure on 7,12-dimethylbenz(a)anthracene-induced mammary
carcinogenesis in two substrains of Sprague-Dawley rats.
Fedrowitz M, Kamino K, Loscher W.
Department of Pharmacology, Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
We have shown previously (S. Thun-Battersby et al., Cancer
Res., 59: 3627-3633, 1999) that power-line frequency (50-Hz) magnetic
fields (MFs) at micro T-flux densities enhance mammary gland tumor
development and growth in the 7,12-dimethylbenz(a)anthracene (DMBA)
model of breast cancer in female Sprague-Dawley (SD) rats. We also
demonstrated that MF exposure results in an enhanced proliferative
activity of the mammary epithelium of SD rats (M. Fedrowitz et al.,
Cancer Res., 62: 1356-1363, 2002), which is a likely explanation for the
cocarcinogenic or tumor-promoting effects of MF exposure in the DMBA
model. However, in contrast with our data, in a similar study conducted
by Battelle in the United States, no evidence for a cocarcinogenic or
tumor-promoting effect of MF exposure was found in the DMBA model in SD
rats (L. E. Anderson et al., Carcinogenesis, 20: 1615-1620, 1999).
Probably the most important difference between our and the Battelle
studies was the use of different substrains of SD rats; the United
States rats were much more susceptible to DMBA than the rats used in our
studies. This prompted us to compare different substrains of SD outbred
rats in our laboratory in respect to MF effects on cell proliferation
in the mammary gland, susceptibility to DMBA-induced mammary cancer, and
MF effects on mammary tumor development and growth in the DMBA model.
The SD substrain (termed "SD1") used in all of our previous studies was
considered MF-sensitive and used for comparison with another substrain
("SD2") obtained from the same breeder. In contrast with SD1 rats, no
enhanced cell proliferation was determined after MF exposure in SD2
rats. MF exposure significantly increased mammary tumor development and
growth in SD1 but not SD2 rats. These data indicate that the genetic
background plays a pivotal role in effects of MF exposure. Different
strains or substrains of rats may serve to evaluate the genetic factors
underlying sensitivity to cocarcinogenic or tumor-promoting effects of
MF exposure.
Cancer Res. 2004 Jan 1;64(1):243-51.
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Hepatocellular Carcinoma: Regional Therapy with a Magnetic
Targeted Carrier Bound to Doxorubicin in a Dual MR Imaging /
Conventional Angiography Suite--Initial Experience with Four Patients.
Wilson MW, Kerlan RK Jr, Fidelman NA, Venook AP, LaBerge JM, Koda J, Gordon RL.
Departments of Radiology and Medicine, University of
California, San Francisco, 505 Parnassus Avenue, Room M-361, San
Francisco, CA 94143.
Four patients with inoperable hepatocellular carcinoma were
treated with a magnetic targeted carrier bound to doxorubicin (MTC-DOX)
by using a joint magnetic resonance (MR) imaging/conventional
angiography system consisting of a 1.5-T short-bore magnet connected to a
C-arm angiography unit by a sliding tabletop. Selective transcatheter
delivery of the MTC-DOX to the hepatic artery was monitored by using
intraprocedural MR imaging, and interim catheter manipulation was
performed with fluoroscopic guidance to optimize agent delivery to the
tumor and minimize delivery to normal tissue. The final fraction of
treated tumor volume ranged from 0.64 to 0.91. The fraction of affected
normal liver volume ranged from 0.07 to 0.30. The dual MR
imaging/conventional angiography system shows promise for directing
magnetically targeted tumor therapies. Copyright RSNA, 2004
Radiology. 2004 Jan;230(1):287-93.
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Principles of magnetodynamic chemotherapy.
Babincova M, Leszczynska D, Sourivong P, Babinec P, Leszczynski J.
Department of Biophysics and Chemical Physics, Comenius University, Mlynska dolina F1, Bratislava 842 48, Slovakia.
Basic principles of a novel method of cancer treatment are
explained. Method is based on the thermal activation of an inactive
prodrug encapsulated in magnetoliposomes via Neel and Brown effects of
inductive heating of subdomain superparamagnetic particles to
sufficiently high temperatures. This principle may be combined with
targeted drug delivery (using constant magnetic field) and controlled
release (using high-frequency magnetic field) of an activated drug
entrapped in magnetoliposomes. Using this method drug may be applied
very selectively in the particular site of organism and this procedure
may be repeated several times using e.g. stealth magnetoliposomes which
are circulating in a blood-stream for several days. Moreover the
magnetoliposomes concentrated by external constant magnetic field in
tumor vasculature may lead to embolic lesions and necrosis of a tumor
body and further the heat produced for thermal activation of a drug
enhances the effect of chemotherapy by local hyperthermic treatment of
neoplastic cells.
Med Hypotheses. 2004 Mar;62(3):375-7.
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Evaluation of systemic chemotherapy with magnetic liposomal doxorubicin and a dipole external electromagnet.
Nobuto H, Sugita T, Kubo T, Shimose S, Yasunaga Y, Murakami T, Ochi M.
Department of Orthopedic Surgery, Division of Clinical
Medical Science, Programs for Applied Biomedicine, Graduate School of
Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
The development of an active drug delivery system is an
attractive approach to increase the targetability of anticancer agents.
In the present study, we examined the efficiency of systemic
chemotherapy with small magnetic liposomes containing doxorubicin
(magnetic DOX liposomes) and an externally applied electromagnetic force
in osteosarcoma-bearing hamsters. Syrian male hamsters inoculated with
osteosarcoma, OS515, in the limb were studied 7 days after inoculation.
The efficiency of this system was evaluated by measuring the tissue
distribution and tumor-suppressing effects of DOX on primary tumor
growth and lung metastases. A DC dipole electromagnet was used, and the
hamster's tumor-bearing limb was placed between 2 poles after the i.v.
administration of liposomes. The dose of DOX and the magnetic field
strength were fixed at 5 mg/kg and 0.4 T, respectively. Administration
of magnetic DOX liposomes followed by 60 min application of magnetic
field produced a 3- to 4-fold higher maximum DOX concentration in the
tumor. This newly designed systemic chemotherapy significantly
suppressed primary tumor growth for at least 2 weeks, though other DOX
treatments also suppressed compared to control. Histologic examination
confirmed a greater antitumor effect of this systemic chemotherapy
compared to standard methods. In addition, this approach significantly
suppressed lung metastases measured at 3 weeks posttreatment. These
results suggest that this systemic chemotherapy can effectively reduce
primary tumor growth and suppress lung metastasis due to increased
targeting of DOX. Such targeted drug delivery for anticancer agents
would provide clinical advantages compared to current methods. Copyright
2004 Wiley-Liss, Inc.
Int J Cancer. 2004 Apr 20;109(4):627-35.
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