The Chemical World This Week
CANCER DRUG DERIVATIVES SHOW PROMISE One of the most widely used anticancer agents is cytosine arabinoside, introduced more than five years ago by Upjohn Co. for treatment of some types of leukemia. A series of derivatives of this nucleoside, newly developed in Japan, are showing markedly greater antileukemic activity and longer duration of activity in the blood in tests on mice. The same tests also indicate less toxicity and thus fewer problems with side .effects compared with cytosine arabinoside itself. The derivatives are iV-acylcytosine arabinosides, synthesized at the technical research laboratory of Asahi Chemical Industries as part of a program to identify and develop anticancer agents. Dr. Hidehiko Kobayashi, the laboratory's director, and Dr. Torao Ishida, who heads its molecular biology group, set up the program two years ago, aiming at the synthesis of unusual nucleic acid derivatives and their preliminary screening for anticancer activity. A synthesis route permitting high specificity of acylation site was worked out and used to produce a series of N4acyl-l-/tf-D-arabinofuranosyl cytosines from cytosine arabinoside and fatty acids. When some of these compounds showed promising results in initial screening, the Japanese Foundation of Cancer Research began detailed testing at its cancer chemotherapy center in Tokyo. The foundation now has confirmed their effectiveness in treating leukemia-inoculated mice. Other test results, still preliminary, suggest that Af-acylcytosine arabinosides may also be active against some forms of solid tumor. (Upjohn's cytosine arabinoside, tradenamed Cytosar, is used primarily for treatment of adult myeloid leukemias. However, it has been used to treat some lymphomas and perhaps Hodgkins disease. Upjohn also has worked with iV4-acyl derivatives but, in general, has found decreased activity.) Results of mice testing, Asahi Chemical notes, show activity against leukemia L-1210 more than four times that of cytosine arabinoside, and more than 100 times its duration of effective concentration in the blood. (L-1210 is a strain of lymphoid leukemia in mice, and is used in drug screening as a model for predicting activity in humans.) 6
C&EN April 21, 1975
Among the N-acylcytosine arabinosides, those with 14 to 22 carbon atoms in the acyl group are considered the most likely to be medically useful, balancing effectiveness, toxicity, and duration of effect. When treated with the C2o and C22 compounds, for example, mice inoculated with L-1210 leukemia survived 3.13 times and 2.41 times as long, respectively, as did untreated mice (at an injection level of 100 mg of agent per kg of body weight). The corresponding figure for cytosine arabinoside was 1.27. Typical reNHCOR,
HOH2.C
0
R-Q»">C2J.
N4-acyl-1-/?-D-arabinofuranosyl-cytosine
suits of tests for duration of activity in the blood stream showed a single injection of 148 mg of the Ci6 compound per kg of body weight was virtually as effective as were nine 22 mg-per-kg injections at daily intervals. All surviving mice in these tests were killed for analysis 30 days after testing began. Survival of L-1210-inoculated mice for such periods is rare, Asahi workers note. About 10 days' life is typical for inoculated mice treated with conventional antileukemia agents. In toxicity tests, mice tolerated as much as 3000 mg per kg of body weight for the C20 and C22 compounds, although their tolerance dropped sharply for the compounds with shorter carbon chains in the acyl group. " Since iV-acylcytosine arabinoside has had a much greater effect on L-1210 than the conventional cytosine arabinoside," says cancer chemotherapy center director Yoshio Sakurai, "it may be reasonably assumed that it will have a similarly significant effect on human cancer. And [its use] may be expected to produce improved results regarding distribution throughout the
human body and excretion therefrom." The center's testing now will move beyond mice to dogs and other animals. Asahi Chemical hopes that clearance as experimental drugs can be obtained within a year's time in Japan so that clinical testing of selected 7V-acylcytosine arabinosides may begin. Meanwhile, the company plans a detailed presentation of its synthesis route in July at the Ninth International Congress of Chemotherapy in London. •
Ag chemicals salvage first quarter As first reports indicated a week ago (C&EN, April 14, page 6), agricultural chemicals were the main prop for the chemical industry during the first business quarter of 1975. A few other areas ran against the recessionary tide—industrial gases, some inorganics such as caustic soda and detergent phosphates, and some biohealth-oriented products. However, most other big-volume product lines, from fibers to plastics to organics and some inorganics, had a very hard winter. How much it helped to be making agricultural chemicals in the first three months of the year comes out in a few figures from Monsanto. Last week the broadly diversified company reported that 78% of its operating (pretax) income in the quarter came from agricultural products, which make up just 28% of sales. Led by highly seasonal pre-emergent herbicides, Monsanto's agricultural chemicals made a fat 52% pretax profit on sales. This farm chemicals bonanza largely saved Monsanto from a drop in net income for the quarter from the year-earlier level. Overall, the company pushed up first-quarter after-tax income 3% to $97.4 million on a sales increase of 9% to $912.7 million. Apart from agricultural chemicals, the other major input to income came from industrial chemicals, which more than doubled operating income from first-quarter 1974. Monsanto cites phosphate and detergent builders for profit contributions. Fully 45% of Monsanto's first-
