Hyperthermic modulation of radiolabelled antibody uptake in a human glioma xenograft and normal tissues.
These experiments investigate the biodistribution of radiolabelled MAb in a human glioma xenograft model after 4 h of local hyperthermia (HT) with a twofold purpose: to maximize the ratio of cumulative isotope activity in tumour relative to normal tissues, and to examine the temperature dependence of the effect. Restrained, unanaesthetized athymic nude mice bearing 150-200 mm3 s.c. human glioma xenografts (D-54 MG) were given 5 micrograms 125I-labelled specific and 131I-labelled non-specific MAb immediately prior to HT (water bath) for 4 h. Cohorts of five animals were killed at 0, 4, 8, 12 and 24 h after HT, and normal and tumour tissues were analysed for activity of each isotope. MAb uptake in tumour was greater with HT than with controls, and greater for specific MAb than for non-specific MAb. Uptake in thyroid was not significantly affected by tumour HT, suggesting that HT does not increase the rate of dehalogenation. Uptake in several other normal tissues away from the heated site was significantly increased (as were reported previously in mice anaesthetized with pentobarbital sodium during treatment; Cope et al. 1990), but the temporal pattern was different from that observed in tumour, suggesting that short-lived isotopes might lead to preferential dose deposition in heated tumour. Doses to various tissues were calculated for isotopes having a range of half-lives; the results clearly indicated that maximum differential in uptake between tumour and normal tissues would occur for isotopes with half-lives < 3 days. A separate series of experiments compared tumour uptake for 40, 42 and 44 degrees C HT. These results demonstrated that 42 and 44 degrees C HT created maximum enhancement in specific antibody uptake over controls. Specific MAb was retained over time in 42 degrees C-heated tumours, whereas significant washout occurred for non-specific MAb, which indicates that MAb retention was due to increased specific binding at this temperature and not vascular damage with antibody trapping. Retention of both specific and non-specific MAb was seen at 44 degrees C, suggesting that vascular damage becomes an important non-specific mechanism for antibody retention at higher temperatures.
Schuster, JM; Zalutsky, MR; Noska, MA; Dodge, R; Friedman, HS; Bigner, DD; Dewhirst, MW
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