Magnetoreception in laboratory mice: sensitivity to extremely low-frequency fields exceeds 33 nT at 30 Hz.

Magnetoreception in the animal kingdom has focused primarily on behavioural responses to the static geomagnetic field and the slow changes in its magnitude and direction as animals navigate/migrate. There has been relatively little attention given to the possibility that weak extremely low-frequency magnetic fields (wELFMF) may affect animal behaviour. Previously, we showed that changes in nociception under an ambient magnetic field-shielded environment may be a good alternative biological endpoint to orientation measurements for investigations into magnetoreception. Here we show that nociception in mice is altered by a 30 Hz field with a peak amplitude more than 1000 times weaker than the static component of the geomagnetic field. When mice are exposed to an ambient magnetic field-shielded environment 1 h a day for five consecutive days, a strong analgesic (i.e. antinociception) response is induced by day 5. Introduction of a static field with an average magnitude of 44 µT (spatial variability of ±3 µT) marginally affects this response, whereas introduction of a 30 Hz time-varying field as weak as 33 nT has a strong effect, reducing the analgesic effect by 60 per cent. Such sensitivity is surprisingly high. Any purported detection mechanisms being considered will need to explain effects at such wELFMF.

The detection threshold for extremely low frequency magnetic fields may be below 1000 nT-Hz in mice.

Previous experiments with mice have shown that a repeated 1 h daily exposure to an ambient magnetic field shielded environment induces analgesia (anti-nociception). This shielding reduces ambient static and extremely low frequency magnetic fields (ELF-MF) by approximately 100 times for frequencies below 120 Hz. To determine the threshold of ELF-MF amplitude that would attenuate or abolish this effect, 30 and 120 Hz magnetic fields were introduced into the shielded environment at peak amplitudes of 25, 50, 100 and 500 nT. At 30 Hz, peak amplitudes of 50, 100, and 500 nT attenuated this effect in proportion to the amplitude magnitude. At 120 Hz, significant attenuation was observed at all amplitudes. Exposures at 10, 60, 100, and 240 Hz with peak amplitudes of 500, 300, 500, and 300 nT, respectively, also attenuated the induced analgesia. No exposure abolished this effect except perhaps at 120 Hz, 500 nT. If the peak amplitude frequency product was kept constant at 6000 nT-Hz for frequencies of 12.5, 25, 50, and 100 Hz, the extent of attenuation was constant, indicating that the detection mechanism is dependent on the nT-Hz product. A plot of effect versus the induced current metric nT-Hz suggests a threshold of ELF-MF detection in mice at or below 1000 nT-Hz.

The means to an end of tumor cell resistance to chemotherapeutic drugs targeting thymidylate synthase: shoot the messenger.

Thymidylate synthase (TS) is an essential enzyme in de novo synthesis of thymidylate, and is required for DNA synthesis and cell proliferation in the absence of exogenous thymidine. As a consequence, TS is a target for anticancer chemotherapy by several drugs, including 5-fluorouracil (5-FU) and raltitrexed (Tomudex), in treatment of colorectal and other tumors. TS overexpression due to increased gene transcription and mRNA translation can mediate drug resistance. Decreased cellular uptake and polyglutamylation of TS-targeting drugs (raltitrexed, for example), increased drug efflux, altered metabolism of cytotoxic drugs (for example, 5-FU), and other events can decrease the effectiveness of TS-targeting drugs. Recent preclinical and clinical studies have addressed the resistance problem by using combinations of different drugs that target TS, or by combining TS-targeting and non-TS-targeting drugs. Our approach has been to circumvent and/or prevent TS overexpression-mediated drug resistance by employing antisense oligodeoxynucleotides (ODNs) to downregulate TS mRNA and protein levels. These studies have revealed that targeting the 3' end of human TS mRNA downregulates TS mRNA and protein, inhibits cell proliferation, and sensitizes HeLa cells to raltitrexed, 5-FU, and 5-fluorodeoxyuridine (5-FUdR) in vitro (Ferguson et al., Br. J Pharmacol. 127, 1777-1786, 1999). In addition, growth of human HT29 colon carcinoma cell explants in immunocompromised mice is inhibited by antisense downregulation of TS (Berg et al., J. Pharmacol. Exp. Therap. 298, 477-484, 2001). TS-overexpressing, 5-FUdR-resistant HeLa cells have been established in order to examine resistance mechanisms and cross-resistance to 5-FU and raltitrexed. Treatment of 5-FUdR-resistant HeLa cells with TS antisense ODN effectively reduces TS mRNA and protein levels, and decreases the IC50 of 5-FUdR by up to 80% (Ferguson et al., Br. J. Pharmacol., 134, 1437-1446, 2001). These results indicate that antisense ODN treatment improves the efficacy of anti-TS chemotherapeutic drugs in vitro and in vivo, and is effective in overcoming tumor cell resistance to these drugs. However, cellular responses to antisense targeting of different TS mRNA domains are complex. In fact, targeting the translation start site (but not other TS mRNA regions) stimulates TS gene transcription (DeMoor et al., E.xp. Cell Res., 243, 11-21, 1998). Distinctive cellular responses to targeting of specific TS mRNA regions provide exciting therapeutic opportunities. Antisense ODN treatment to modulate TS activity, in combination with TS-targeting chemotherapeutic drugs, has the potential to be an effective anti-tumor therapy.