RESEARCH
Caged Isotopes May Help Fight Cancer 3IVTs microspheres can be injected into blood supply of affected organs Radioisotopes injected into the bloodstream may be useful in treating cancers of some organs. Behind the new technique are Minnesota Mining & Manufacturing's Radiating Microspheres (C&EN, Oct. 3, 1960, page 20)— tiny ceramic spheres containing radioisotopes. The microspheres are injected into the main artery that supplies the affected organ and become trapped in the smaller blood vessels where radiation from the isotope does its work. Preliminary animal tests done by Dr. John F. Perry. Jr., and associates (who conceived the technique) at the University of Minnesota medical school indicate that the microspheres can be fairly uniformly distributed in the liver and lungs. So far, no serious adverse effects caused by the microspheres themselves have been seen except in kidneys of test animals. Both Dr. Perry and 3M president Herbert P. Buetow point out that tests to date have been very preliminary and have been done on healthy animals, not cancerous ones. Mr. Buetow cautions that "we do not want to mislead anyone into thinking that we believe these preliminary experiments have produced any sudden and miraculous cure/' Extends Technique. Despite the huge effort being made to find chemotherapeutic agents for treating cancer (C&EN, Oct. 12, 1959, page 53), surgery and irradiation remain the best means available today. Surgery offers the advantage of physical removal of the cancer and, if performed early enough, can lead to cures. But surgery is limited to fairly localized tumors and its value is sharply reduced if the cancer has spread. Irradiation by x-rays often is used to treat skin and other surface cancers, for treating cancers in organs not amenable to surgery, and as an adjunct to surgery in certain tumors. But cancer-killing doses of radiation from DISTRIBUTION. Autoradiographs show how microspheres containing yttrium-90 distribute themselves in the liver (top), lung (center), and kidney of animals 40
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external sources may affect tissues outside the target area. Radioisotopes have also been used as irradiation sources to treat cancer. Needles containing radioisotopes or colloidal forms of radioisotopes are put into body cavities. 3M's Radiating Microspheres containing cesium-137 are now being evaluated for use in implant needles. In internal organs such as the liver, for example, technical problems prevent using needles as irradiation sources and surface irradiation from colloidal radioisotopes is not very effective. 3M sees its microspheres as offering an ideal medium for handling radioisotopes. The spheres are insoluble in most media including body fluids. Tests show practically no radioactive material is leached out of them. 3M says it can control the size of its microspheres with great accuracy, even in low micron sizes. And a wide variety of isotopes can be used in the spheres, with the amount of radiation emitted closely controlled. Recently, treatment of cancers by perfusing affected areas with chemotherapeutic agents has shown some success. Since, to date, irradiation is more effective than chemicals in treating cancer, perfusing an organ with radioactive material looms as a logical extension of this technique. Check Safety. Dr. Perry and his group, looking for ways of readily introducing radioactive materials into cancerous organs, started their studies by using microspheres made by 3M. The study had three preliminary objectives: to determine if the ceramic spheres themselves cause any damage by blocking blood vessels, to find out if the microspheres readily localize in the intended organ and don't escape into the general circulation, and to study irradiation effects from isotopeladen microspheres. Isotope-free microspheres about 60 microns in diameter were first injected into main arteries supplying kidneys, livers, and lungs of healthy dogs. After 10 days, these organs were inspected and microscopic sections made. Livers and lungs showed no adverse
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effects. But six of 11 kidneys showed sen ere damage. Apparently, anatomical peculiarities of the kidney's blood vessels are such that they are readily blocked with resulting severe damage to the organ. Arterial networks in other organs studied seem to have free enough intercommunication of small arterioles, thus preventing damage to the organ. There is no evidence of toxicity from the microspheres. Microspheres in the 60-micron range seem to be big enough to prevent their passing readily into general circulation. Tests on healthy dogs treated with microspheres containing chromium-51 showed that maximum loss occurred when the hind limb was injected; a \(/c escape of spheres into general circulation was detected with a scintillation counter. Escape from the lung was 0 . 0 9 ^ , from the liver, 0.16 r /r, and from the kidneys, 0.02',Y . Distribution of microspheres was fairly uniform in all organs but the kidney, Dr. Perry says. Autoradiographs of organs injected with microspheres containing yttrium-90 or samarium-153 show a slight tendency for the spheres to lodge centrally in the lung and liver. But generally, their distribution was throughout the organ except in the kidney where spheres lodged in the periphery due to stoppage by the tiny arterioles. Conventional clinical tests show that when spheres containing yttrium-90 in dosages up to 16 millicuries were injected into liver and lung, there were no significant changes from normal in the peripheral blood and no alteration of liver function. Clinical Testing. These preliminary tests merely determine the mechanical feasibility and short-term safety of the new technique, Dr. Perry says. Clinically, the technique has been used in two patients suffering from metastic cancer of the liver. Microspheres containing barium-140 were used. No ill effects appeared from injection of the microspheres into the liver's blood circulation. More extensive testing is needed to establish the effectiveness of the treatment against cancers. Also unknown are long range safety aspects and which isotopes and radiation dosages are best suited for use in patients. Among intriguing aspects still awaiting study is that there's a good possibility that mixtures of isotopes—perhaps alpha, beta, and gamma emitters—can be used to gain maximum effect with minimum dosages. 42
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Leuconitriles: Two Photoreaction Paths IBM work clarifies mechanism of dye formation by photoreactions of triarylmethyl leuconitriles The mechanism of the photoreactions of the triarylmethyl leuconitriles has been worked out by Dr. A. H. Sporer at International Business Machines, San Jose, Calif. These compounds can be used as photographic materials which produce a visible image immediately on irradiation with no subsequent development. The photoionization of such compounds as malachite green leuconitrile by ultraviolet radiation to form the corresponding dye has been known for many years. It has also been known that this reaction depends upon the dielectric constant of the solvent. In solvents with a dielectric constant above 4.5 (such as ethanol), dye formation occurs readily. In cyclohexane and other low dielectric constant solvents, irradiation produces a photoreaction but no dye formation. Dr. Sporer says that there are two independent photoreactions. One, which occurs only in high dielectric constant solvents, involves hvdrolytic cleavage of the nitrile group and leads to the dye—a triarylmethyl cation— via a triarylmethyl free radical. The other, which takes place in all sol-
vents, involves homolytic cleavage of substituents on the amine nitrogen, he adds. The quantum yield of the dye-forming reaction had previously been reported as essentially unity. The cleavage reaction was overlooked entirely because its quantum yield is only 0.02; this is within the experimental error of the determinations on the dyeforming reaction. Yet another type of reaction takes place with Victoria blue B leuconitrile. When this compound is dissolved in ethanol and irradiated at room temperature, it produces intense fluorescence but almost no dye formation. Dr. Sporer finds that about half of the radiation is absorbed by the dimethylaniline groups. The other half is absorbed by the IV-phenyl-T-naphthylamine group and it produces fluorescence. But the radiation absorbed by the dimethylaniline groups produces neither cleavage nor dyeforming ionization. Instead, this energy is transferred to the N-phenyl1-naphthylamine group and it too is emitted as fluorescence.
Two Photoreactions Are Independent R = C6H5malachite green R = N-phenyl-lnaphthylamine— Victoria blue B
