Murine EMT-6 Carcinoma: High Therapeutic Efficacy of Microbeam Radiation Therapy

Abstract

Microbeam radiation therapy is an experimental modality using parallel arrays of thin (<100 micro m) slices of synchrotron-generated X rays (microplanar beams, microbeams). We used EMT-6 murine mammary carcinoma subcutaneously inoculated in the hind legs of mice to compare the therapeutic efficacies of single-fraction, unidirectional (1) "co-planar" microbeams (an array of vertically oriented microplanar beams), (2) "cross-planar" microbeams (two arrays of parallel microbeams propagated in the same direction, one with vertically and the other with horizontally oriented microplanar beams), and (3) seamless (broad) beams from the same synchrotron source. The microbeams were 90 micro m wide and were spaced 300 micro m on center; the median energy in all beams was 100 or 118 keV. Tumor ablation rates were 4/8, 4/8 and 6/7 for a 410-, 520- and 650-Gy in-slice cross-planar microbeam dose, respectively, and 1/8, 3/8, 3/7 and 6/8 for a 23-, 30-, 38- and 45-Gy broad-beam dose, respectively. When the data were pooled from the three highest doses (same average tumor ablations of 50-60%), the incidences of normal-tissue acute toxicity (moist desquamation and epilation) and delayed toxicity (failure of hair regrowth) were significantly lower for cross-planar microbeams than broad beams (P < 0.025). Furthermore, for the highest doses in these two groups, which also had the same tumor ablation rate (>75%), not only were the above toxicities lower for the cross-planar microbeams than for the broad beams (P < 0.02), but severe leg dysfunction was also lower (P < 0.003). These findings suggest that single-fraction microbeams can ablate tumors at high rates with relatively little normal-tissue toxicity.

Interlaced x-ray microplanar beams: A radiosurgery approach with clinical potential

“…Prior studies have shown that irradiation of rats with 9LGS malignant brain tumors k (2,7,15) and mice with s.c. EMT-6 murine mammary carcinomas (8) and SCCVII murine squamous cell carcinoma (14) with unidirectional, single-fraction, high dose, thin-beam MRT preferentially damages the tumors while sparing healthy tissue. This unexpected and unique preferential tumoricidal effect has become the hallmark of the MRT approach.…”

Emerging neurosurgical applications of synchrotron-generated microbeams

“…The tolerance of the vascular bed to high dose microbeam irradiation has been clearly demonstrated by the lack of extravasation of dyes administered to the experimental animals, which remained confined in the vessels after irradiation from 12h until three months following 1000 Gy [27]. This radioresistance phenomenon was not observed in 9L glioma microvessels, confirming the presence of a differential response to between normal and tumour brain tissues in rodents, an effect that can have significant clinical applications [19]. The neoplastic vasculature appears to be unable to replicate the fast repair of the segments hit by the peak dose, facilitating the development of radionecrosis over the irradiated tumor [12,20,28].…”

“…Unidirectional irradiation using microbeam arrays has been delivered to adult rat brain [11,13,15,16], suckling rats cerebellum [16], piglets cerebellum [1], duckling embryo brain [18], skin and muscle of the mouse leg [19,20], rat leg [21] and rat spinal cord [12]. The exceptional resistance of the normal-tissue to high dose microbeam irradiation with no evidence of late tissue effects [12,22,23,24] lead to the development of a new concept in radiobiology, the tissue sparing effect, described in the next paragraph.…”

“…Most of the experimental activity performed until now has been focused on the study of the effects of arrays of parallel microbeams [4,5,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][28][29][30]. MRT has been applied to several tumor models including intracerebral gliosarcoma (9LGS) in rats [11,13,30], murine mammary carcinoma (EMT-6) [19] and human squamous-cell carcinoma (SCCVII) in mouse and rat [9,20]. Rats bearing the intracranial 9L gliosarcoma irradiated anteroposteriorly with arrays composed of 27 gm thick microbeams spaced 100 gm on-center showed a clear survival advantage after MRT: 4 out of 14 rats irradiated at 625 Gy incident doses were longterm survivors with little brain damage revealed in histopathology [11].…”

Synchrotron Radiation Therapy from a Medical Physics point of view

“…At the ESRF the center-to-center distances between beams range from 100 to 400 µm in MRT and it is 1200 µm in MBRT. The preclinical studies in MRT indicate a remarkable healthy tissue sparing capability [10,11,12,13,14,15] and the ablation of highly aggressive tumours in several animal models [16,17,18,19,20,21,22]. In MBRT, the first preclinical studies indicate that minibeams still keep (part) of the healthy tissue sparing capability observed in MRT [9,23].…”