Letter to the Editor

(CANCER RESEARCH 28. 2188-2169,October 1968]

Arthropod Antineoplastic Agents'

New antineoplastic agents of novel structure isolated from (saline solution) on the first day of tumor transplant and con microorganism and plant sources have continued to provide tinued for each of 5 days. Tumor growth was measured on the leads toward clinically useful cancer chemotherapeutic agents. 10th day. Isolation and characterization of the active compo Actinomycin C-i (la), streptonigrin (ib), mitomycin C (ic), nent(s) of Melanitis leda determinata Butler is in progress, and and daunomycin (id) serve as examples of antitumor agents similar examination of other arthropod members is also under from microorganisms. Inspecting the corresponding structures way. Several other fractions from Asian butterflies, e.g., Catop suggests that certain quinones and related ir-electron systems silia crocale Cramer, Ixias pyrene insignis Butler, Pieris rapae may be valuable starting points for designing other antiturnor crvavora, Prioneris thestylis Dbldy., and Yoma sabina vasuki agents. Similar conclusions may be reached by reviewing struc Doherty, have shown similar antineoplastic activity. In the tures of new cell growth inhibitors isolated from plant sources Insecta class we have also found such diverse organisms as (2) . Here, epoxy groups and extended ir-electron systems in beetles (e.g., Allomyrina dichotomus) and grasshoppers (e.g., volving lactones also appear important. Thus, the relatively an Acrididae species) producing substances which inhibit small percentage of known plant and microorganism species growth of the Walker 256 carcinoma. so far evaluated in terms of antineoplastic activity have pro From information now at hand, the arthropods appear a duced several useful clinical agents and valuable information new and interesting source of potentially useful antineoplastic for structural manipulation. With the prospect of uncovering agents. other classes of unusual compounds (from natural sources) potentially useful in cancer chemotherapy, we have undertaken Acknowledgments study of arthropod components. For the same reasons, we have also begun an extensive investigation of marine invertebrates We are particularly indebted to J. F. Day, Dr. R. R. Engle, B. (including some marine vertebrates). J. Abbott, C. H. Duplissa, A. H. Albert, Dr. J. C. Knight, and Arthropods have experienced a long history of use in prim Dr. K. S. Brown for very helpful contributions to the investiga itive medical practice (3 a-d) . For example, Tarantula cubensis tion. Also, we are grateful to P. D. Wells, G. J. Lauten, B. R. has been claimed to be â€œusefulin malignant ulcersâ€• and can Houghton, C. T. Day, E. L. Koeneman, other members of our tharidin (4) , a component of various blister beetle species, has laboratories and to the specialists of the Insect Identification and been purported to have antitumor activity. To assess the Introduction Branch, U.S. Department of Agriculture, Beltsville, arthropods as sources for potentially useful antineoplastic Md., and the Department of Entomology, Smithsonian Institution, Washington, D.C. for their contributions. agents, we have undertaken evaluation of species from the Arthropoda classes Insecta, Arachnida, Crustacea, and Myria poda. To our knowledge, no prior systematic investigation of References arthropods for antineoplastic agents has been undertaken. The 1. (a) Goldberg, I. H. Mode of Action of Antibiotics. II. Drugs class Insecta alone presently comprises nearly 900,000 species Affecting Nucleic Acid and Protein Synthesis. Am. J. Med., and the order Lepidoptera (butterflies and moths) approx 89: 722â€”752,1965; (b) Rao, K. V., Biemann, K., and Wood imately 100,000 species distributed among 22 families. A sub ward, R. B. The Structure of Streponigrin. J. Am. Chem. Soc., stantial number of arthropod species, particularly representa 85: 2532â€”2533, 1963 ; (c) Stevens, C. L., Taylor, K. G., Munk, tive of the Insecta, Arachnida, and Myriapoda classes, have M. E., Marshall, W. S., Noll, K., Shah, G. D., Shah, L. G., been examined in our laboratories. Specimens so far studied and Uzu, K. Chemistry and Structure of Mitomycin C. J. Med. were from North and South America as well as Asia. Chem., 8: 1â€”10,1964; (d) Arcamone, F., Cassinelli, G., Fran We now wish to report that, to date, a small number have cesehi, G., Orezzi, P., and Mondelli, R. The Total Absolute given encouraging results. The butterfly Melanitis leda deter Configuration of Daunomycin. Tetrahedron Letters, 80: 3353â€” minata Butler provides an illustration. In random-bred albino 3356, 1968. rats bearing the Walker 256 carcinoma (subcutaneous) , a @J5% 2. For leading references refer to : (a) Kupchan, S. M., Heming ethanol extract of the butterfly (prepared following pretreat way, R. J., Werner, D., Karim, A., McPhail, A. T., and Sim, ment of the butterfly with petroleum ether and 50% ethanol) G. A. Vernolepin, A Novel Elamanolide Dilactone Tumor In hibitor From Vernonia hymenolepis. J. Am. Chem. Soc., 90: led to 65â€”73% inhibition of tumor growth at dose levels of 3596â€”3597,1968;(b) Bianchi, E., Culvenor, C. C. J., and Loder, 400â€”600 mg/kg. The material was given intraperitoneally J. W. Psilostachyin, A Cytotoxic Constituent of Ambrosia artemisilfolia L. Australian J. Chem., 21 : 1109, 1968; (c) Kup 1 This investigation was supported by USPHS Research Grant chan, S. M., Hemingway, J. C., Cassady, J. M., Knox, J. R., CAâ€”10612--01from the National Cancer Institute, NIH. McPhail, A. T., and Sim, G. A. The Isolation and Structural Received June 25, 1968; accepted July 19, 1968. Elucidation of Euparotin Acetate, A Novel Guaianolide Tumor

2168 CANCER RESEARCH VOL. 28

Inhibitor From Eupatorium rotundifolium. J. Am. Chem. Soc., 4. Walter, W. G., and Cole, J. F. Isolation of Cantharidin From 89: 465-466, 1967; (d) Knight, J. C., Pettit, G. R., and Herald, Epicauta pestigera. J. Pharm. Sci., 56: 174â€”176,1967. C. L. Isobufadienolides.Chem. Commun., 445-446,1967; (e) Kupchan, S. M., Cassady, J. M., Kelsey, J. E., Schnoes, H. K., George R. Pettit Smith, D. H., and Burlingame, A. L. Structural Elucidation and High-Resolution Mass Spectrometry of Gaillardin, A New Department of Chemistry Cytotoxic Sesquiterpene Lactone. J. Am. Chem. Soc., 88: 5292â€” Arizona State University 5302, 1966. Tempe, Arizona 85281 3. ia) Riley, W. A., and Johannsen, 0. A. Medical Entomology. New York : McGraw-Hill, 1938; (b) Herms, W. B. Medical Jonathan L. Hartwell Entomology. New York : The Macmillan Company, 1939; (c) Harry B. Wood Cowan, F. Curious Facts in the History of Insects. Philadelphia: Cafl@er Chemotherapy National Service Center J. B. Lippincott Co., 1965 ; (d) Clausen, L. W. Insect Fact and National Cancer Institute Folidore. New York : The Macmillan Company, 1954. Bethesda, Maryland 20014

OCTOBER 1968 2169

George R. Pettit, Jonathan L. Hartwell and Harry B. Wood

Cancer Res 1968;28:2168-2169.

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