Nuclear Medicine Gets Friendlier

 Experimental therapies seek to poison just the disease 

"I looked like a concentration camp survivor," recalls Sue Spenceley, describing the day 2 years ago when she arrived at the Arlington (Texas) Cancer Center. Ravaged by both Hodgkin's disease and the myriad therapies that had been directed against this lymphoma over the previous 8 years, the 5'8" woman weighed just 113 pounds and had barely enough energy to walk. 

 As director of medical staff support at what she describes as "a very savvy hospital" in Orange County, Calif., "I had physicians at my door - literally." Yet they hadn't been able to stop her disease. 

 Altogether, she suffered through 13 different regimens of radiation and chemotherapy. Some so enervated her that she would be out of breath after climbing a few stairs. Others rendered her vulnerable to infection or caused nerve damage to her fingers and feet that still persists after 7 years. What a surprise, then, to find no unpleasantness associated with her Texas therapy. "Not only did it not wipe me out, but it actually allowed me to begin recovering from the aftermath of my last chemotherapy," she says. 

 With her cancer finally in check, she says, "there's nothing I wouldn't do." Last Christmas, she "skied like crazy and hiked." This therapy, she insists, "has given me my life back." 

 Spenceley's treatment represents a new and evolving wave of nuclear medicine that's letting physicians target increasing amounts of radiation against disease, while reducing the toxic effects on patients. Explains Huibert M. Vriesendorp, the radiation oncologist spearheading the trial that Spenceley is participating in, the overall goal is not only to improve the efficacy of cancer treatment but finally to make it "patient-friendly." 

 Other clinicians are applying the strategy to heart disease and arthritis.

 Most of these new therapies rely on an expanding arsenal of antibodies chosen for their ability to find and bind to some cell surface protein peculiar to a patient's cancer. When injected into the patient, the antibody attaches to the cancer cells and, because it is linked to a radioisotope, becomes a lethal weapon. As the isotope decays, emitting pent-up energy in the form of ionizing radiation, the cancer gets hammered. 

 These new nuclear therapies minimize harm to normal tissue both by using antibodies to ferry the isotopes specifically to cancer cells and, increasingly, by employing isotopes that emit beta or alpha particles. Because they can travel only short distances in tissue - typically 5 millimeters or less for betas and less than one-thousandth that distance for alphas - there's far less risk than with X rays that these types of radiation will spill over to cancerfree tissue. 

 Ultimately, the goal of many of these new therapies is to match the scope of the high-powered but short-range radioactive particles to the size of the tumor being targeted, explains Thomas S. Tenforde of the Energy Department's Pacific Northwest National Laboratory (PNNL) in Richland, Wash. 

 To target clumps consisting of no more than a few cells, typical of leukemias or wandering metastatic seeds of solid tumors, alphas might be the preferred choice. For larger tumors, physicians might choose the more penetrating betas. One day, doctors may even be able to select from a family of beta emitters with different energies - and therapeutic ranges - to tailor the radiation's reach to a particular cancer's size.

 A radioisotope is a single atom of an unstable element. An antibody is a much larger, Y-shaped protein. Neither has any intrinsic interest in entering a permanent relationship with the other. To bring together the reluctant mates chemically, biologists and chemists have had to engineer molecular-scale matchmakers-cages and linker molecules. 

 The idea is to trap isotope atoms within molecular cages, then use the linker molecules to bond one or more cages onto each antibody. The challenge, explains Tenforde, whose team is working to create new radiopharmaceuticals, has been building cages that exhibit a strong attraction for a specific isotope - indeed, a preference for it over any chemically related kin that might be found in the body. 

 For instance, in early April, Darrell R. Fisher of PNNL finally constructed a cage for the alpha emitter radium-223, a decay product of actinium-227. "It's a major scientific breakthrough that will finally make it possible to use this [very short-lived] alpha emitter," Fisher declares. He points out that the achievement was realized "only after 10 years of work, including 7 years of synthesizing compounds and running stability tests on them." 

 So far, just a small number of successful isotope-antibody marriages have been arranged. Some of the earliest bind iodine-131, an isotope that emits low-energy gamma radiation along with a beta particle. 

 Dana C. Matthews of the Fred Hutchinson Cancer Research Center in Seattle has been exploring this isotope for 6 years in teenagers and adults scheduled to receive bone marrow transplants to arrest advanced leukemias. Her therapy uses an antibody that targets the CD-45 protein on white blood cells and most leukemias. 

 The standard treatment for these patients includes whole-body irradiation with an external beam of gamma rays. In a study begun several years ago to test how well the new therapy would be tolerated, 30 patients with advanced leukemia were given the maximum tolerable amount of external radiation, along with enough antibody-linked radioisotope to deliver 30 to 90 percent more radiation to the cancerous tissue. Though 5-year survival for patients with such an advanced cancer would ordinarily be around 25 percent, "we've gotten almost 50 percent survival," Matthews says. 

 Her group is planning studies to see whether isotopes without gamma radiation might offer even greater benefits. 

 While the iodine's gamma radiation is not high, Matthews notes, it does require that treated patients remain isolated in lead-insulated rooms for 4 to 10 days until the radioactive iodine decays to a point at which it no longer poses a health risk to hospital staff or visitors. Adult patients may be able to gain sufficient comfort from talking to family by phone or across chest-high shields at the door, but young children need a parent's touch, she says. "So as a pediatric oncologist, I'm very interested in getting away from the gamma component." 

 One gammafree isotope under investigation is yttrium-90. Over the last 8 years, Vriesendorp has been using this isotope, which emits solely betas, to treat some 130 Hodgkin's patients who have failed to benefit from all previous therapies. His regimen delivers two injections of the isotope, 1 week apart, on an outpatient basis. Even in these advanced cases, he notes, "we get a very good tumor response in two-thirds [of the patients]. The tumors shrink." Vriesendorp uses radioisotope purified from nuclear waste. 

 At the Memorial Sloan-Kettering Cancer Center in New York, David A. Scheinberg has turned to bismuth-213, which emits only alpha radiation, to treat leukemia, again on an outpatient basis. 

 For nearly a decade, he had tried iodine-131, but high doses killed blood-making cells, necessitating a bone marrow transplant. "That's not a feasible scheme for the majority of patients, who are either too old or lack a marrow donor," he says. 

"The beauty of the alpha particle," he observes, "is that it travels only about 50 microns - which is approximately three to five cell diameters." Though his initial trial is designed to identify maximum tolerable doses for treatment, not to assess efficacy, "we've already seen significant antileukemic activity in the patients we've treated," he told Science News.

 To date, these antibody therapies have been directed primarily against leukemias and lymphomas, Vriesendorp notes. Not only are these cancers generally smaller and more sensitive to radiation poisoning than solid tumors, they're also bathed in the blood that can ferry the injected isotopes. 

 Programs are now under way to adapt these treatments to solid cancers. The Arlington team, for instance, is marrying yttrium-90 to a large antibody known as IGM. 

"IGM is so big that it will not leave the bloodstream," Vriesendorp notes, "so it's not good where you need to use the vascular system to get into a tumor." It does show promise for destroying metastases in confined spaces, such as ovarian tumors that have spread to the peritoneal cavity. The soluble IGM-isotope pair can also be injected directly into a tumor. Using nude mice, "we've put it in the middle of a cancer," he says, "and over the next day or two it diffused throughout the tumor." 

 The IGM therapy is slated to be tested on people later this year, initially in patients with breast, colon, ovarian, or head and neck cancers. In a year or two, Scheinberg hopes to begin human trials with antibody-directed alpha-emitting isotopes targeted to tiny metastases from breast, prostate, or other solid cancers. 

 Antibodies aren't necessary for the beta therapy to relieve suffering in patients with tumors growing in bone. Radiologist Edward Silberstein of the University of Cincinnati Medical Center has been investigating a host of radionuclides with a natural affinity for bone, including samarium-153, strontium-89, and rhenium-186. Yttrium-90 and others are being tested in Europe. 

 His studies on about 150 patients indicate that each of the isotopes he's tried, "though not a cure," appears "quite effective" - reducing up to 80 percent of pain. 

"We sometimes reduce the pain before the tumor [shrinks]," so some of the radiation's palliative effects must come from destroying white blood cells or other biological agents responsible for causing or signaling pain, he says.

 Compared to cancers, normal tissues tend to be more sensitive to radiation and chemotherapy. Thus, Vriesendorp notes, oncologists have adopted a "no pain, no gain" philosophy. Internally targeted radiation promises a new alternative, he says-"therapies that don't have to be given at such an industrial strength that they bring the patients to the intensive care unit and close to death." 

 Indeed, Spenceley argues, "if you could learn you had cancer - as horrible as that is - and know that this treatment option was available, then the diagnosis would not be as ugly as it is today."