By David N. Leff

No one knows what legendary surgeon first said, "The operation was a success, but the patient died."

That epitaph certainly applied to the early decades of organ transplantation, beginning with the first experimental kidney grafts in 1954. Those pioneer organ recipients succumbed not so much to the surgery as to its aftermath: organ rejection by an outraged immune system.

Early immunosuppressant drugs either failed to prevent rejection, or worked all too well at knocking out the patient's shield against lethal infection. This grim Catch-22 held back the entire field of organ transplantation, until the cusp of the 1980s.

In 1975, immunologist Jean Borel, at the then-Sandoz Pharma AG, in Basel, Switzerland, discovered a compound synthesized by a fungus named Tolypocladium inflatum Gams. Borel was looking for an antibiotic; instead, he discovered an immunosuppressant with a difference.

Rather than clobbering a mouse's entire immune defenses, this novel fungal metabolite - which Sandoz called cyclosporine - inhibited only one subset of one arm of the immune system, namely T lymphocyte helper cells. It left transplant recipients with a decent modicum of immune protection against invading pathogens, while sparing donor organs from instant or delayed graft rejection.

Cyclosporine became, and remains, a mainstay of organ transplantation, enabling the field to move boldly from replacing one kidney (where its opposite number served as a safety net) to liver, heart, bone marrow and eventually multiple-organ replacement. In December 1983, the FDA approved its use as a standard concomitant of organ transplantation.

To be sure, cyclosporine had one serious side effect - kidney toxicity. Transplant surgeons had to tailor its dosage to minimize this risk of kidney failure without unduly courting the danger of graft rejection. (See BioWorld Today, June 10, 1998, p. 1)

Now, a different consequence of cyclosporine administration has surfaced, in yesterday's issue of Nature, dated Feb. 11, 1999. The paper's title spells out the drug's unsuspected effect: "Cyclosporine induces cancer progression by a cell-autonomous mechanism." Its senior author is transplant physician Manikkam Suthanthiran, at Cornell University's College of Medicine, in New York. He is chief of transplant medicine at the Cornell-affiliated New York Presbyterian Hospital.

However, his paper is not a wake-up call to abandon cyclosporine as a premier safeguard against organ rejection.

Cyclosporine's Cancer Connection? Not To Worry

"We think this is not a cause for alarm," Suthanthiran told BioWorld Today. "It would be terrible if transplant patients read this and get worried. We think our finding is actually a reason for hope, in the sense that there may a metabolic pathway we might want to block. In particular, inhibiting the hyperexpression of transforming growth factor-beta (TGF-b) may be useful to prevent cancer progression.

"And this may not be just for organ transplantation alone," he continued. "In other types of cancer, if the tumor cells make a lot of TGF-b, it may be a way by which a cancer cell evades the immune system."

Suthanthiran and his co-authors propose that cyclosporine generates excessive concentrations of TGF-b, "It's a very important cytokine in terms of wound repair," he said. "An excess can give you trouble. In the mouse, when you knock out the TGF-b gene, the animal dies within two to three weeks, of a fatal multifocal inflammatory disease. But TGF-b is not all bad. I think of it as being like blood pressure. If you have the right levels of TGF-b, it's very beneficial, whereas an excess is harmful. Hypertension or hypotension are both bad; normal blood pressure is good. TGF-b is like that."

Malignancies Common After Transplants

"Malignancy is a common and dreaded complication following organ transplantation," the Nature paper starts off.

Transplant teams, the article points out, commonly attribute these invasive and aggressive cancers to impairment of the organ recipient's immune surveillance system, which patrols the body for invading antigens. The Cornell co-authors report "a mechanism for the heightened malignancy that is independent of host immunity," and attributable to the effects of cyclosporine.

"I think cyclosporine is a very useful drug," Suthanthiran declared. "It has improved patient and graft survival. We are not suggesting that cyclosporine increases the incidence of cancer. What we are suggesting is that maybe the reason transplant patients get cancer is that it, and drugs like it, suppress the immune system, which then is not able to fight the cancer. Even if a transplant candidate has a past history of cancer, unless he or she is two years free of malignancy, that patient will not be transplanted.

"Clearly," he continued, "transplant recipients get more cancer. A recent study showed that 10 years after receiving new organs, maybe 13 percent have a neoplasm, and that risk increases with time. By 15 years, it's 20 percent, and 20 years out, 40 percent. Most of these malignancies are skin cancers, and in these patients, tumors tend to be more aggressive."

He said the increased cancer risk "is not very peculiar to cyclosporine alone. A number of pre-cyclosporine immunosuppressants, such as prednisone and imuran, were also associated with an Increased incidence of cancer in transplant patients. In many such cancers, physicians would reduce or stop the immunosuppressive therapy. And that's a double-edged sword, because maybe it would cause the tumor process to regress, but it may be bad for the transplanted organ. Because when you put in a transplant, most recipients require lifelong anti-rejection therapy."

Suthanthiran and his co-authors injected SCID-beige mice, which lack an intact immune system, with human cancer cells, then administered cyclosporine. "Those tumors obviously grew in these mice," he recounted. "Then, when we treated them with cyclosporine, the number of their tumors went up. Typically, we counted 100 tumor nodules in untreated mice, and 150 nodules in the treated ones."

They were able to block this increase, using an antibody to TGF-b.

"We interpreted this effect to mean," Suthanthiran said, "that the increase in TGF-b expression, its concentration, contributed at least in part to the rise in tumor nodule number. Because the mice were immunodeficient, this was not a conventional mechanism people think about. The immuno-surveillance theory holds that your T cells and B cells are keeping the cancer in check. These mice didn't have T cells or B cells or natural killer cells."

The Cornell transplanter sees his team's finding as "a new mechanism for cancer progression. We have several ideas how best to inhibit the excess expression of TGF-b, perhaps better than the antibody we reported in the paper. Blocking it may be beneficial to organ recipients, and also to other cancer patients. There may be gene-therapy approaches as well," Suthanthiran concluded, "and other drug candidates that can can block this expression. That's what we plan to do."