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Correspondence re: C. G. Ferreira et al., Apoptosis: Target of Cancer Therapy. Clin. Cancer Res., 8: 2024–2034, 2002.

Department of Medical Oncology, Nuclear Medicine and Pharmacy, University Hospital Groningen, 9700 RB Groningen, the Netherlands

Ferreira et al. (1) report on the potential value of TRAIL for cancer treatment in their interesting review on apoptosis and ways to exploit this process to treat cancer. As indicated by these authors the death receptor ligand TRAIL¹ is probably an interesting drug to treat cancer patients. However, they describe that there is an important interspecies variability in the response to TRAIL and, therefore, the safety of this ligand for clinical use. On the basis of new information, this considered interspecies variability all seems to be because of differences in the preparation of the recombinant TRAIL. Because of the potential major interest for TRAIL in the clinic we would like to summarize this issue and underscore the potential of TRAIL for using it in the clinic. In vitro TRAIL induces apoptosis in tumor cells but not in nontransformed, normal cells (2) . The first report on the in vivo use of TRAIL came from Walczak et al. (3) . They used a leucine zipper form of human and murine TRAIL to promote and stabilize the formation of TRAIL trimers. In contrast to the fulminant hepatotoxicity of leucine zipper FasL in vivo, administration of either recombinant human TRAIL or recombinant murine TRAIL was not toxic to normal tissues of mice (4) . A soluble recombinant form of TRAIL without a leucine-zipper that was active against a variety of human cancer cell lines did not induce toxicity in normal human cell types. Repeated i.v. injections with this TRAIL in cynomolgus monkeys did not cause detectable toxicity to tissues and organs examined (4) . Antitumor activity without systemic toxicity was demonstrated in mice bearing solid tumors (4) . The same active soluble TRAIL was tested in chimpanzees that received a single i.v. bolus dose of TRAIL (5) . No toxicity was observed; however, the chimpanzees have not been sacrificed. Serial serum samples were collected in chimpanzees and analyzed for immunoreactive TRAIL by ELISA and for bioactivity of TRAIL. Data from individual animals was fitted using either a one- or two-compartment model, which suggested that in mice, rats, cynomolgus monkeys, and chimpanzees TRAIL was primarily cleared by the kidneys (5) . Previous studies demonstrated His-tag TRAIL or FLAG-tag TRAIL-induced toxicity after incubation of cultured human hepatocytes, cultured primary human aorta and pulmonary artery smooth muscle cells, or human brain tissue slices with these compounds (6, 7, 8) . Lawrence et al. (9) in collaboration with the group that published the TRAIL-induced toxicity on hepatocytes, thereafter showed that native recombinant human TRAIL without His-tag and with Zinc was nontoxic for cultured human hepatocytes in contrast to His-tag TRAIL.

Together this information points to the fact that the preparation of TRAIL without His-tag is crucial for the absence of toxicity to normal human cells.

It has been reported recently that TRAIL can be present in serum of AIDS patients (10) . Furthermore, we have demonstrated detectable levels of TRAIL in plasma samples in a number of different diseases. This underscores the fact that the human body can tolerate certain levels of TRAIL.

Hopefully the initial confusion concerning TRAIL will soon disappear and open up ways to clinical trials with recombinant human TRAIL.

FOOTNOTES

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The abbreviations used are: TRAIL, tumor necrosis factor-related apoptosis-inducing ligand.

Received 8/26/02; accepted 10/ 3/02.

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