In vivo cytotoxicity assays with 111In-labeled tumor cells: comparison with [125I]iododeoxyuridine-labeled cells and effects of chelators and inoculation site.

The fate of cells inoculated in nude mice can be determined using human tumor cells prelabeled with 111In oxine (111InOx). To facilitate elimination of extracellular 111In released from killed cells, an appropriate metal chelating agent is administered to the host mice. With calcium disodium edetate administered by various routes, highly significant differences in the rates of 111In loss were observed for viable compared to killed cells after i.p. or i.m. inoculation. Radioactivity was eliminated at similar rates for mice bearing viable cells labeled with 111In or with [125I]iododeoxyuridine (125IUdR). For killed cells, 111In was eliminated somewhat less efficiently than 125I. The 111In-prelabeling method allows facile and sensitive determination of host-mediated cytotoxicity for inoculated tumor cells.

Prediction of anticancer activity by tumor uptake of radiolabeled monoclonal antibody.

A novel and sensitive method is described for rapid detection of anticancer drug efficacy against human tumor xenografts in nude mice. CA or BRO human melanoma cells were inoculated i.m. in nude mice, which then were treated with saline or cytotoxic agents. After injection of 111In-labeled 9.2.27 antimelanoma monoclonal antibody, the site of tumor inoculation and the contralateral non-tumor site were excised from sacrificed mice. Relatively lower 111In uptake in the area of tumor inoculation correlated with prevention or delay of tumor growth in identically treated counterpart mice.

Effectiveness of anticancer drugs determined in nude mice inoculated with [125I]5-iodo-2'-deoxyuridine-prelabeled human melanoma cells.

Anticancer drugs were tested on NIH-2 nude mice inoculated ip with BRO human melanoma cells, which are rapidly lethal for these hosts. Criteria for drug activity were a) increased host survival and b) an increased rate of radioactivity loss from mice bearing BRO cells prelabeled with [125I]5-iodo-2'-deoxyuridine. Diphtheria toxin, which is selectively toxic to human cells compared to mouse cells, prolonged host survival and accelerated 125I elimination in a dose-dependent manner. Drugs that increased the rate of 125I loss compared to the rate of untreated mice also prolonged the lives of treated mice. With one exception, drugs that did not accelerate 125I elimination had little or no effect on the length of survival.

Antitumor activity and minimal toxicity of concentrated thymidine infused in nude mice.

To avoid infusing large volumes of fluid while treating patients with the standard thymidine solution (30 g/liter), it may be possible to administer this drug in more concentrated form. At 25 degrees C, thymidine is saturating at a concentration of 52 g/liter of 0.6% NaCl solution, and the thymidine concentration at saturation increases with temperature. Nude mice were infused at 29 degrees C with thymidine (60 or 72 g/liter) in cycles consisting of 4 to 5 days infusion followed by 9 days rest. Therapeutically effective doses of concentrated thymidine did not cause significant mortality in mice, and weight loss attributable to treatment was small and reversible. Significant growth inhibition of CA 1 human melanoma heterotransplants was observed after 3 treatment cycles. After 4 or 5 cycles, tumor responses were obtained in 7 mice (6 complete responses) of 12 inoculated with this tumor. These results show that concentrated thymidine solutions are highly effective against human tumor heterotransplants in nude mice and suggest that clinical use of concentrated thymidine may allow practical administration of maximum tolerated doses of this drug.

Determination of cytotoxicity in vivo using 111indium-labeled human tumor cells.

Loss of radioactivity from nude mice was determined after inoculation of human tumor cells prelabeled with [111In]indium oxine (111InOx). Elimination of 111In was increased somewhat by treating the mice with diphtheria toxin (DT), which is toxic selectively for human cells compared to mice. Calcium disodium edetate (CaNa2EDTA), a metal chelating agent, facilitated elimination of 111In and increased the difference in the rates of loss of radioactivity from mice bearing viable compared to DT-killed cells.