Human leukemia sensitive to L-asparaginase
Henry Moore's "Nuclear Energy" Conflicting emotions son announced, is willing to allow the International Atomic Energy Agency to inspect all U.S. nuclear installations except military ones, if other nations will allow inspections, too. The offer could be a major incentive toward the nuclear nonproliferation treaty which has been bogged down in negotiations at the disarmament conference in Geneva. The U.S. offer was warmly welcomed by the gathering and by President Saragat of Italy, who spoke to the scientists following Mr. Johnson's address. But perhaps the member of the Chicago audience who welcomed it most warmly was A. Sigvard Eklund, secretary-general of the International Atomic Energy Agency. Earlier in the day, Mr. Eklund warned that if a nonproliferation treaty were not forthcoming from the disarmament conference by the middle of 1968, the momentum generated for the treaty would likely be lost. Not all was pessimism, however. The beneficial aspects of atomic energy, particularly the burgeoning growth of nuclear power throughout the world, were recounted by several speakers,- including Alvin Weinberg, director of Oak Ridge National Laboratory. All the conflicting emotions that are generated by the power of the atom became visible at the climax of the celebration. At 3:36 P.M., 25 years to the minute since that first chain reaction, Mrs. Enrico Fermi, widow of the physicist, unveiled a sculpture created by noted artist Henry Moore A monumental for the occasion. bronze form titled "Nuclear Energy," the sculpture marks the location of the squash court in the since-demolished Stagg field stands.
Leukemias in man are sensitive to treatment with the enzyme L-asparaginase, according to Dr. Herbert F. Oettgen and coworkers at Memorial Sloan-Kettering Cancer Center in New York City. Addressing the annual meeting of the American Association of Hematology last week in Toronto, Dr. Oettgen said that six out of 12 patients with leukemia or lymphoma responded favorably to this kind of treatment. The preliminary study provides the first clinical data on the enzyme's effects in humans. An earlier cooperative research effort by Cornell University Medical College, New York University School of Medicine, University of Delaware, and Sloan-Kettering Institute scientists had shown that large doses of L-asparaginase can permanently cure transplanted leukemia in mice. This novel approach to cancer chemotherapy is based on the observation that certain kinds of cancer cells require an external source of the amino acid L-asparagine. Normal cells do not. These dependent cancer cells must acquire L-asparagine from extracellular fluid. Treatment with L-asparaginase causes extracellular L-asparaginase to hydrolyze to L-aspartic acid. This deprives the cancer cells of their external source of asparagine and the cells die. The enzyme—a polypeptide with a molecular weight
Dr. Herbert F. Oettgen Encouraging, but
of 106,000—does not appear to interfere with the intracellular metabolism of normal cells. In the present study, all five patients with acute lymphoblastic leukemia responded favorably. One patient with acute myeloblasts leukemia showed a temporary response; three others with the same diagnosis did not respond. The remaining patients—one with acute monoblastic leukemia and two with lymphosarcoma— did not respond either. Side effects included fever, nausea, and weight loss. Whether these were due to the enzyme or impurities isn't known. The Memorial Sloan-Kettering research workers say that they are encouraged by these results, but that the available amount of purified enzyme was and still is insufficient for optimal dosage treatment. The enzyme is obtained from the bacterium Escherichia coli. The crude material is highly toxic. Its purification is difficult, slow, and very expensive. An optimal dose for a mouse is about 100 times the amount required for temporary remission. Because of its scarcity, Dr. Oettgen and his coworkers could not administer correspondingly high amounts to the humans treated. Dr. Oettgen's coworkers include Dr. Lloyd J. Old, Edward A. Boyse, Harold A. Campbell, Frederick S. Philips, Bayard D. Clarkson, Lisa Tallal, Robert D. Leeper, Morton K. Schwartz, and Jae Ho Kim.
Butadiene-phenol reaction gives linear dimerization of diene When butadiene and phenol interact in the presence of a soluble palladium catalyst and a base, linear dimerization of the diene occurs and the phenol adds on at the terminal carbon atom. The phenoxy moiety can be removed from the reaction product to make 1,3,7-octatriene in high yield. This dimer of butadiene is difficult to make by other routes, notes Dr. Edgar J. Smutny of Shell Development Co., Emeryville, Calif. [/. Am. Chem. Soc, 89? 6793 (1967); U.S. Patent 3,267,169]. The reaction is a general one. It takes place between conjugated dienes and a variety of nucleophiles that contain -OH and -NH groups. It also provides a convenient path to linear dimers of conjugated dienes that couldn't be made before. Many of these may turn out to be valuable intermediates for a broad spectrum of industrial products such as resins and surface coatings. The unique feature of the reaction is the fact that the backbone of the butadiene dimer is linear. "This is DEC. 11, 1967 C&EN
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Linear dimerization Difficult any other way
truly remarkable/' in Dr. Smutny's opinion, "because some change in structure, be it branching or cyclization, usually accompanies oligomerization of conjugated dienes by other routes." He points to these other unusual as pects of the reaction: • It's simple, fast, and takes place equally well in the presence or ab sence of solvents. • Changes in temperature or pres sure don't affect it. • Yields are high and essentially free of by-products. • Complexes of other Group VIII metals catalyze the reaction equally well. The catalysts aren't afiFected by oxygen, water, and other common "poisons." • Nucleophiles such as alcohols, amines, and organic acids also enter into the reaction with butadiene. Like phenols, these add to the terminal car bon atom of the dimer. In a typical experiment, Dr. Smutny and his collaborators, Harold Chung, Dr. Kenneth C. Dewhirst, Dr. Willi Keim, and Dr. Thomas M. Shryne, mix phenol (1.0 mole) and butadiene (4.0 moles) together at 0° C. for several hours in the presence of 7r-allyl pal ladium chloride and sodium phenoxide. A 96% conversion of phenol to phenoxyoctadiene takes place in the process. The reaction product consists of 95% l-phenoxy-2,7-octadiene and 5% 3-phenoxy-2,7-octadiene. Vacuum distillation of this mixture in the pres ence of triphenylphosphine yields high-purity 1,3,7-octatriene and phe nol. The Shell Development team believes that the role of triphenylphos phine is to stabilize and prolong the catalyst life. If triphenylphosphine isn't added, palladium metal sepa rates out and catalytic decomposition 22 C&EN DEC. 11, 1967
to octatriene stops, Dr. Smutny notes. In practically all cases, the reaction stops at the dimer stage. Conversion to dimer can be carried out continu ously by recycling the phenol and re acting it with additional fresh diene monomer. The findings of Dr. S. Takahashi, Dr. T. Shibano, and Dr. N. Hagihara of Osaka University substantiate Shell Development's discovery. Using a soluble palladium catalyst system, the Japanese workers have dimerized bu tadiene to 1,3,7-octatriene [Tetrahed ron Letters, 2451 (1967)]. What probably happens is that the diene first dimerizes around the cat alyst, Dr. Smutny conjectures. The nucleophile then interacts with the re sulting complex in the presence of excess diene. The result, in effect, is an anti-Markovnikov addition of nu cleophile to the linear dimer, he points out.
Other investigators have prepared solutions that probably contain various sulfenium ions but under conditions that are not amenable to organic syn theses, Dr. Helmkamp points out. He and his students—Dennis Owsley, Wayne Barnes, and Howard Cassey— were interested in using the reactive ions in organic reactions. One obvious application, for example, would be to react them with olefins as an alter nate route to the alkylated episulfides. Sulfenium ions, Dr. Helmkamp ex plains, have long been postulated in polar additions of sulfenyl halides to olefins and acetylenes, and in disulfide exchanges in acid solutions and in bio logical systems. In the system devised by the UC group, methanesulfenyl bromide, RSBr, was reacted with silver 2,4,6-trinitrobenzenesulfonate (TNBS) in a mixture of nitromethane and dichloromethane. In some runs, acetonitrile was also present. When acetonitrile was present, the resulting solution was conductive. Without it, the solution was a weak conductor. In either case, whatever species was present was able to transfer its sulfenium portion in a reaction with an olefin. The conductivity data, along with Ν MR spectra, lead Dr. Helmkamp to theorize that the methanesulfenyl ion reacts with acetonitrile to form an other ion, RS-N=C-CH 3 , and it is this ion that reacts in subsequent re actions rather than free sulfenyl ions. Without acetonitrile, he believes, the sulfenyl ions react with the trinitrobenzenesulfonate ions to give the nonconducting species RS-OS0 2 -trinitrophenyl. When acetonitrile is added to this, the conductivity of the solution goes up, indicating that the ionic com pound is being formed. Thus, Dr. Helmkamp has tentatively concluded that he is not dealing with free sulfen-
Organic solutions may yield ions that behave like sulfenium ions It is possible in organic solutions to get reactive ions that behave like sulfen ium ions, RS+, but they are probably not free sulfenium ions, according to Dr. George K. Helmkamp of the Uni versity of California, Riverside. Speak ing at the Symposium on Sulfenyl Chemistry, sponsored by the IntraScience Research Foundation in Santa Monica, Calif., Dr. Helmkamp said evidence indicates that the reactive RS+ is very likely bonded to another compound that can be displaced easily by nucleophilic reactants. He also described an interesting outgrowth of his research in this area—an organic reaction that appears to fix molecular nitrogen.
Dr. Helmkamp (left) and Owsley Transfer agents
