Effect of clinical levels of misonidazole on the response of tumour and normal tissues in the mouse to alkylating agents.

Experiments were carried out to determine whether the enhancement of alkylating-agent cytotoxicity seen after large single doses of misonidazole (MISO) in mouse tumours can also be achieved by prolonged exposure to low MISO levels similar to those which can be tolerated clinically. The level in mouse blood plasma could be maintained at about 100 micrograms/ml for 7 h by injecting small doses of MISO every 1/2 h. The effect of this treatment in combination with cyclophosphamide (CY) or melphalan (L-PAM) was studied in the RIF-1 tumour, using regrowth delay and cell-survival cloning assays. In each case, prolonged exposure to low levels of MISO gave enhancement ratios very close to those obtained with a large single dose. ERs of 1.6-2.0 were obtained with CY and 1.8-2.2 with L-PAM over the range of alkylating-agent doses used. In experiments with CY the response of 2 normal-tissue systems, marrow and WBC count, was also studied. No significant enhancement of CY damage occurred in either case. In the L-PAM experiments the LD50/30 and WBC counts were determined as normal-tissue end points. Multiple MISO had no effect. Our results show that levels of MISO which can be achieved safely in man yield good enhancement of the tumour cytotoxicity of 2 widely used chemotherapeutic agents without increasing the damage to normal tissues

Seasonal dynamics and mortality rates of Calanus helgolandicus over two years at a station in the English Channel

The stage-specific abundance and egg production rates of Calanus helgolandicus were determined on a near-weekly basis over 2 yr at a 50 m deep station in the SW English Channel (Stn L4). Mortality rates were derived using a vertical life-table approach across eggs, nauplii and also the CV–adult stage pair. The results demonstrate strong seasonal patterns in the mortality rates of egg and nauplii and the CV–adult stage pair, but with different relative rates and somewhat different seasonalities. Mortality was highest in the egg and egg–NI stages, averaging 6.1 and ~1.5 d–1, respectively, with the percentage surviving through the egg–NI stage pair often <<10%. Although the instantaneous removal rate of eggs was significantly related to adult abundance (p < 0.001, r2 = 0.221), densities of adult C. helgolandicus seemed too low to account for these rates. Examination of the relationship between CV–adult female mortality and the abundance of the dominant invertebrate predators revealed statistically significant relationships (p < 0.001 r2 = 0.276 for chaetognaths; p < 0.001 r2 = 0.125 for siphonophores); however, the variability explained by temperature was much higher (p < 0.001 r2 = 0.652). The egg–NI and NI–NII stage pairs also showed a highly statistically significant positive relationship between mortality and temperature. For the first time we compared mortality rates for egg–NI using 2 vertical methods—one using measurements of egg and NI abundance (Method A) the other using egg production rates and NI abundance (Method B)—and found the two to be similar, although Method B gave higher values. Finally, as many mortality equations do not consider the bias resulting from the presence of eggs incapable of hatching in the field, we derived and applied new equations for mortality of eggs and egg–NI (Method A) that incorporated egg hatching success. At low hatching success or low mortality rates, this correction can alter estimates of mortality rates significantly

Changes in nerve conduction velocity in the mouse after acute and chronic administration of nitroimidazoles.

The effect of the nitroimidazoles misonidazole, Ro-05-9963, RGW-608 and metronidazole on nerve conduction velocity (NCV) were measured in the anaesthetized mouse. The compounds were administered by i.p. injection either as a single dose of 1 mg/g (only 0.5 mg/g for RGW-608) or in 36 fractions of 0.15 mg/g over 18 days (only 4 fractions in 2 days for RGW-608). After single doses a reduction in nerve conduction velocity was seen with all the compounds except metronidazole, which had no significant effect. During chronic exposure, a reduction in NCV occurred towards the end of the course of injections. All compounds produced an effect, although RGW-608 was the most neurotoxic, giving the largest reduction in NCV after only 4 injections. After the end of chronic exposure to misonidazole, Ro-05-9963 and metronidazole, recovery to normal took 2-3 weeks

Gold nanoparticles as novel agents for cancer therapy

Gold nanoparticles are emerging as promising agents for cancer therapy and are being investigated as drug carriers, photothermal agents, contrast agents and radiosensitisers. This review introduces the field of nanotechnology with a focus on recent gold nanoparticle research which has led to early-phase clinical trials. In particular, the pre-clinical evidence for gold nanoparticles as sensitisers with ionising radiation in vitro and in vivo at kilovoltage and megavoltage energies is discussed