By David N. Leff

Clinical oncologists define their dosing strategy as striving to attain a ¿therapeutic index.¿ Many of their patients ¿ probably through clenched teeth ¿ call this the ultimate Catch-22.

Navigating the narrow path between the cliff of treatment and the abyss of side effects, chemotherapy and radiation therapy can and do achieve striking tumor-shrinking cures. But at the price of agonizing adverse side effects, from transient baldness to unbearable nausea and diarrhea to unremitting discomfort. These often cause patients to throw in the towel of treatment; for them the cure is worse than the cause.

Damage to the gastrointestinal tract, lung and brain has long been the dose-limiting factor for chemotherapy and radiation therapy. But until now, scientists did not know which cells targeted within those organs were responsible for the lethal responses.

Endocrinologist Richard Kolesnick, who heads the Laboratory of Signal Transduction at the Memorial Sloan-Kettering Cancer Center in New York, is senior author of a paper in the current issue of Science, dated July 13, 2001. Its title: ¿Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice.¿

¿The finding, which challenges dogma, at least in the GI tract,¿ Kolesnick told BioWorld Today, ¿is that the target of this lethal radiotoxicity, which limits the effective use of both radiation and chemotherapy for the treatment of cancer, is in fact the small microscopic blood vessels ¿ not the putative, dogma-dictated, stem cells required for the life of that organ. The death of these microvessels,¿ he continued, ¿presumably causes collapse of the microcirculation, and without circulating blood, the tissues and stem cells that support them will not survive.

¿For 20 or 25 years,¿ Kolesnick observed, ¿we researchers have been investigating science, mostly at the cellular or the subcellular level ¿ the biochemical and molecular biological level. Now, with the advent of the new biology, we can ask questions at the tissue level, which is far more complex than the cellular level. In fact, the interaction of cells in a tissue is more than the additivity of all the cells in that tissue. So the new concept involves trying to understand what in any particular tissue ¿ in this case the GI tract ¿ might be the responsive element to radiotherapy.¿

Stem Cell Dogma Challenged On Two Fronts

¿There is a challenge to dogma in another sense also,¿ pointed out radiation oncologist Zvi Fuks, a lead co-author of the Science paper. ¿The challenge is that for 40 years, we have assumed that radiation targets are primarily epithelial and tumor cells, with the endothelial vascular effects being secondary. That was largely because most of the investigations were done in the test tube, not in vivo. But now that we are looking at organized tissue, we believe that the most sensitive target of radiation, at least in some cases, might be the microvasculature ¿ the tumor¿s blood supply ¿ rather than stem cells or tumor cells.

¿Whether it¿s a normal tissue or a neoplastic tissue,¿ Fuks told BioWorld Today, ¿tissue is tissue, and if it depends on the microvasculature in one, it¿s essentially proof of principle that it could depend on the microvasculature in another. In other words, by providing evidence that the microvasculature was regulating radiation response in the GI tract, by analogy it could be regulating radiation response in other tissues, such as tumors.

¿This new focus on the microvasculature as a tumor target is not only challenging dogma,¿ he pointed out, ¿it also defines the specific cells for pharmacological agents that would modulate radiation effects precisely, rather than multiple mechanisms that might happen at the tumor level or the stem cell level.

¿One of the reasons Judah Folkman, the angiogenesis pioneer,¿ Fuks continued, ¿was so interested in our paper that he was willing to write a commentary for it, has to do with the fact that we have provided proof of principle in the gastrointestinal tract for the notion that it¿s the vasculature ¿ the tumor¿s angiogenesis ¿ that¿s the target of cancer therapy. This is very similar to what Folkman¿s saying ¿ that microvasculature supports the tumor, and the tumor supports the microvasculature.¿¿ (Folkman¿s editorial bears the title: ¿What does radiotherapy do to endothelial cells?¿)

¿What we have done,¿ Fuks recounted, ¿was to test the sensitivity of the GI tract with single high-dose radiation. What would be of greater interest would be if we now moved the paradigm to a more clinically relevant setting, namely with what we term fractionated radiation. In this, we treat a limited area of the body with small daily doses of radiation and increase them gradually. Whether the same effects on microvasculature would be observed under this mode of therapy still needs to be investigated. We are running these experiments at the present time. Obviously, if we can recapitulate the same phenomena in fractionated radiation, it would have a tremendous potential for clinical application.¿

In the team¿s most recent in vivo experiments, Fuks related, ¿We treated mice with total body radiation and monitored the outcomes by autopsies of the animals that were dying. We escalated the radiation dose from nontoxic to lethal, and followed its effects on the survival of those mice with and without pharmacological injections of basic fibroblast growth factor [bFGF].¿

This drug blocked the cell-signaling acid sphingomyelinase pathway, and prevented GI tract damage in the mice. Hence, they could receive higher radiation doses ¿ with implications for human cancer therapy.

Fribroblast Growth Factor Receptor Is Key

To which Kolesnick added: ¿The key finding in this paper is that the protection afforded by the bFGF must be delivered to the small blood vessels because they are the major component containing that factor¿s receptors. The putative epithelial stem cells in the intestinal crypts appear not to contain any bFGF receptors, and therefore cannot be direct targets of radiotherapy protection.

¿The question that¿s been brought up here,¿ Kolesnick observed, ¿is what¿s the relevance of this? Perhaps, to improving the therapeutic index, to getting the therapeutic advantage. Can we in fact improve the therapeutic outcome either by protecting the microvasculature of the normal tissues, or by deprotecting the microvasculature of the tumor? That¿s what we¿re working on right now.¿