Changing focus: applying antisense to nuclear medicine imaging.

The practice of antisense chemotherapy employs single-chain DNA–RNA oligonucleotides designed to interfere with the expression of a gene crucial to the disease under treatment. Although clinical research in this field is not much more than a decade old, progress has been impressive. At ‘Antisense ’98’, a symposium held in London in October 1998, presentations by representatives from both industry and academia underscored the depth and breadth of current research1xAntisense 98: work in progress. Crooke, S.T. et al. Nat. Biotechnol. 1998; 16: 1319–1321Crossref | PubMedSee all References1. Fresh in the minds of all participants and, indeed, the biotechnology field in general, was the first antisense therapeutic to reach the market – formivirsen (Vitravene), a drug manufactured by Isis Pharmaceuticals Inc. (Carlsbad, CA, USA) for the treatment of cytomegalovirus retinitis in patients with AIDS. Additional therapeutics are in late-stage clinical trials. True, the mechanism of action has not been, and possibly cannot be, established as antisense in these patient studies2xMaking sense of antisense. Smaglik, P. The Scientist. 1998; 12: 1See all References2 but results of in vitro and animal in vivo studies provide evidence of an antisense mechanism.The object of this letter is to suggest that antisense now be considered as a means to localize radioactivity for imaging (and radiotherapy) of disease3xSee all References3. Happily, the task of applying antisense to imaging will benefit from much of the past and present research in chemotherapy because many of the requirements overlap. For example, both imaging and chemotherapy require in vivo stability of antisense oligonucleotides against nucleases and, in particular, both require transport across cell membranes in adequate amounts and in a form that permits the subsequent targeting of mRNAs. Unfortunately, requirements diverge in the case of many other key properties; for example, the rapid localization and prolonged retention of the radiolabeled antisense oligonucleotides in the target, and rapid clearance kinetics of the radiolabel elsewhere, are requirements unique to nuclear medicine. But again, antisense imaging is blessed with several advantages that should simplify its development. For example, the large number of mRNA targets per cell is an advantage for imaging even while being a disadvantage for chemotherapy. In addition, chemical toxicity should be less of a concern because imaging dosages will almost certainly be much lower (however, radiotoxicities might become an issue); this will have the added advantage of lower cost. Furthermore, whereas successful antisense chemotherapy might depend upon RNase H enzymes, antisense imaging will not be restricted to those oligonucleotides that are RNase H substrates. Unfortunately, several factors might complicate the development of antisense imaging. For example, the radiolabel might interfere with cell membrane transport and in situ hybridization. Furthermore, the diseases that might be of greatest interest for imaging are not necessarily those now being targeted for chemotherapy.Effort towards developing antisense imaging is thus far nonexistent compared to the extensive investigations of antisense chemotherapy. The development of antisense chemotherapy has been accomplished largely within industrial laboratories, in which literally hundreds of oligonucleotide analogues have been synthesized and tested in a continuing search for suitable second- and third-generation oligonucleotides. Furthermore, the most effective antisense oligonucleotides are now being selected from the results of testing a sizable series of oligonucleotides with sequences around that of the targeted mRNA. The high costs involved in these studies mean that future efforts towards the development of antisense imaging might require industrial support. However, collaborations between academic investigators, experts in radiopharmaceutical development and investigators from the antisense chemotherapy industry might be needed to speed the development of antisense imaging.No doubt the development of antisense imaging will continue to benefit from improvements made within the antisense chemotherapy field. Nevertheless, as the above will make clear, a separate and considerable effort will be required to optimize this approach for imaging. The potential of specifically targeting virtually any disease or normal tissue with radioactivity for imaging and, possibly, radiotherapy should make this effort worthwhile. In support of this suggestion is the economic potential of radiopharmaceuticals: the worldwide market for nuclear medicine imaging agents has been projected to reach US $2.0 billion in 2001 (from US $1.3 billion in 1997). The market for radiotherapy agents is smaller but also increasing rapidly and projected to reach about US $0.7 billion in 2001 (C.W. Seidel, pers. commun.). Although these numbers might be small compared to the market for chemotherapeutics, they are not inconsiderable.