Thirty-two presentations were grouped into five general categories: Terrestrial Sources for Active Constituents and Lead Structures (8presentations); Marine Sources for Active Constituents and Lead Structures (3 presentations); Antimicrobial and Antiturnour Compounds (6 presentations); Natural Products as Experimental Tools and Leads in Drug Design (8 presentations); CNS-Active Natural Products in Drug Development (7 presentations). The individual presentations are generally well referenced and provide both a useful summary of the respective topics and an effective entry into the primary literature. The two stated objectives of this Symposium were to focus on the successful conversion of natural products into therapeutic agents and to focus on areas in this research field which are underdeveloped. The organizers achieved these objectives. The casual reader may be more impressed initially with the efforts toward satisfying the first objective. This reaction reflects a number of excellent presentations which illustrate diverse approaches or manipulations that have been utilized successfully to obtain clinically or scientifically useful agents. However, a person realizes on further reflection that these successful examples are also models for future efforts to expand into underdeveloped areas or leads. Contemporary and emerging technologies offer unusual promise for serious investigations in the natural product field. This volume will be of interest to established investigators in the natural product field, but its greatest contribution will probably come as a single-volume, general-approach reference for repeated study by students aspiring to scientific careers in natural product development. Lynn R. Brady School of Pharmacy University of Washington Seattle, WA 98195
Folate Antagonists as Therapeutic Agents, vol. 1: Biochemistry, Molecular Actions, and Synthetic Design; vol. 2: Pharmacology, Experimental and Clinical Therapeutics. Edited by F. M. Sirotnak, J. J. Burchall, W. D. Ensminger, and J. A. Montgomery. Academic Press, Orlando, FL 32887. 1984. Vol. 1: 367 + xv pp. 23.4 x 16 Vol. cm. ISBN 0-12-646901-6. $69.50 (f 49.00). ISBN 0-12-646902-4. 23.4 x 16 cm. 2: 303 + xv pp. $59.50. (f 42.00). The 40-year history of folate antagonists has been marked by striking successes and curious anomalies, both of which emerge clearly from this highly readable pair of volumes. Therapeutic success came early with the antineoplastic agent methotrexate (1948) and the antimalarial pyrimethamine (1951), followed within 10 years by the antibacterial trimethoprim. Subsequent progress has been continuous in the fields of molecular biology of drug-receptor interactions (discussed by Freisheim and Matthews), biochemistry (reviewed by Kisliuk), and pharmacology (aspects of which are discussed in several chapters). Among the anomalies is the fact that during the past quarter-century, this wealth of basic research has not been reflected in development‘ of more effective drugs. That this has not been for want of synthetic effort is attested by chapters by Montgomery and Piper and by Werbel. The mechanism of antitumor selectivity is the subject of one whole chapter (Sirotnak and DeGraw) and portions of other chapters. The rapid and extensive recent advances in our understanding of the selective toxicity of
antifolates provide grounds for optimism that improved antifolates may yet be developed. The chapter on experimental cancer chemotherapy (Hutchison and Schmid) was of particular interest for its historical perspective, and Hitchings and Baccanari tell the parallel history of folate antagonists as antimicrobial agents. Information on two newer compounds currently in clinical trials as anticancer agents may be found in the chapters by Sirotnak and DeGraw (10-ethyl-10-deazaaminopterin) and Werbel (trimetrexate). However, there is no mention of the interesting new class of antifolates (exemplified by 5,8dideaza-10-propargylfolate)that act by inhibition of thymidylate synthase. Two basic misunderstandings of pharmacological theory have permeated the antifolate literature from its origins to the present day. The first is the idea that tight-binding reversible inhibitors may be treated as “stoichiometric.” That this is not the case in intact cells, and why not, is explained in a chapter on “The Biochemical Basis for Methotrexate Cytotoxicity.” However, the chapter on “Pharmacokinetics of Methotrexate” perpetuates the error of treating dihydrofolate reductase inhibition by methotrexate as irreversible. Any model that does not allow for displacement of enzyme-bound methotrexate by accumulated dihydrofolate cannot correctly describe its cellular pharmacology. The other recurring error in the literature is the idea of sequential blockade as an explanation of synergistic drug interactions. That combinations of sulfa drugs with trimethoprim have synergistic antibacterial activity is undeniable, but the reason for this has nothing to do with sequential inhibition. Hitchings and Baccanari mention, but do not clarify, this issue in a section (“Concept and Application of Sequentia Blockade”)which, despite its misleading title, sets the record straight by pointing out that the combined inhibition of the thymidylate synthase cycle and of a reaction feeding into the cycle are the essential features for synergism. They fail to acknowledge that this important principle was established by Grindey et al. several years before the cited paper by Harvey. Occasional errors and omissions aside, these volumes maintain a high standard of scientific content and literary clarity. Most of the chapters review the literature through 1983. The greater portion of the work is concerned with anticancer agents, but 4 of the 18 chapters deal exclusively with antibacterial and antiprotozoal drugs, and one with psoriasis. The two volumes contain separate, and useful, subject indices. When contemplating book purchases, I ask myself: “If I had to throw something out of my library to make room for these books, would I still buy them?” In this case, the answer is “definitely.” This pair of volumes is likely to be the standard work on its subject for the next 10 years. Robert C. Jackson Warner-Lambert/Parke-Davis Pharmaceutical Research Division Ann Arbor, MI 48105
Materials Used in Pharmaceutical Formulation. Critical Reports on Applied Chemistry, vol. 6. Edited by A. T. Florence. Blackwell Scientific Publications, 706 Couper Street, Palo Alto, CA 94301. 1984. 161 pp. $35.00. This volume contains four quite detailed and entirely separate monographs: “Materials Used in the Film Coating Journal of Pharmaceutical Sciences / 905 Vol. 74, No. 8,August 1985
of Oral Dosage Forms” by Rowe; “Tablet Lubricants” by York; “Polymeric Materials Used in Drug Delivery Systems” by Wood; “Properties of Fatty Alcohol Mixed Emulsifiers and Emulsifying Waxes” by Eccleston. All four sections are clearly written and generally well-referenced, with some references as late as 1983 included. The index is quite adequate, the figures are well presented, and the book appears to be commendably free of typographical errors. In some cases, the reader may wonder why certain areas are not discussed but, in general, the coverage is adequate. All four authors are from the United Kingdom, and for North American readers the British flavor is, at times, somewhat of a limitation, but this is not a major problem. This type of book is, by its very nature, likely to be only of interest to a specialized clientele. Also, because of rapid technological change, it will probably soon become seriously out of date. However, it can still be recommended as a reference text for all involved in pharmaceutical formulation. It will also have value for those specifically concerned with evaluating the function of components in modern drugdelivery systems. Christopher T. Rhodes Department of Pharmaceutics College of Pharmacy University of Rhode Island Kingston, RI 02881
MonoclonalAntibodies and Cancer. Edited by George L. Marcel Dekker, Inc., 270 Madison Avenue, Wright, Jr. New York, NY 10016. 1984. 444 pp.
This monograph is part of the “Immunology Series” edited by Noel R. Rose, constituting volume 23. The text is directed toward assembling the current knowledge and techniques related to antibody targeting for a variety of solid tumors and leukemias. The use of these techniques in clinical diagnosis of cancer, the staging and prognosis of the disease state, and the use of monoclonal antibodies as therapeutic agents against cancer growth are highlighted. The text is divided into the following general areas: 1. The application of monoclonal antibodies to human clinical cancers surveying the techniques for somatic cell hybridization for the purpose of producing monoclonal antibodies to specific tumor antigens, the problems in the mass production of monoclonal antibodies, potential application of the monoclonal antibodies for human diagnosis including early detection, differential diagnosis (benign versus malignant), staging and grading of the tumor, increase o r loss of normal antigens, quantitative analysis of tumor antigens, and monitoring of micrometastatic lesions, therapy with either monoclonal antibodies alone or with those coupled with drugs, toxin, o r isotopes, and the immune system of the patient and ratio of immunocompetent cells. 2. The current status of monoclonal antibodies designed for melanoma-associated antigens, neuroblastoma antigens, glioma tumor antigens, human mammary carcinoma antigens, human lung tumor antigens, osteogenic sarcoma antigens, human leukemic antigens, human ovarian carcinoma antigens, and human prostate tumor antigens was reviewed extensively. Included in each of these chapters was the characteristics of the monoclonal antibody, whether it was specific for tumor antigen or normal host tissue antigens, and separate epitopes of a given antigen or antigens which were common t o more than one organ or tissue in the body. The targeting of the antibody for specific use as a 906 / Journal of Pharmaceutical Sciences Vol. 74, No. 8,August 1985
therapeutic agent against cancer cell growth was also evaluated including cancer cell uptake, specificity for malignant cells, cross-reactivity with other host antigens, and coupling of the antibody with toxin, isotopes, or cancer chemotherapy agents. Each of these chapters attempted to assess for the reader the actual value of each of these monoclonal antibodies against human cancers in the clinical testing with both successful trials as well as those which failed. The authors attempted to discuss the pros and cons of the use of antibodies derived for cancer cells. 3. The heterogeneity of tumor-associated macromolecules, e.g., carcinoembryonic antigen (CEA) and alpha fetal protein (AFP), was discussed, where the characteristics of the CEA and AFP antigens were delineated using monoclonal anti-CEA or anti-AFP antibodies. The use of monoclonal antibodies for radioimmunodetection of cancer in the clinic was reported as well as for a number of animal models. Methods of enhancing passive immunotherapy using monoclonal antibodies as well as methods of minimizing tumor cell escape, modulating cell-surface antigens, maximizing host effect on cells and complement-mediated cell cytolysis, and optimizing pharmalogical coupled antibodies were delineated briefly. This is one of the few texts which attempts to assess individual tumor antigens for the purpose of designing monoclonal antibodies as cancer agents. As the text indicates, this is now a realistic possibility for human cancer patient therapy; nevertheless, the authors of the various chapters have attempted to be extremely objective in the sense that areas of failure with monoclonal antibody therapy as well as acute problems in the techniques are discussed, fully recognizing this is a technique which is in its genesis. I think this volume is a concise overview ~f the current merits of the antibody-directed cancer therapy. The text is well illustrated and it offers an extensive compilation of numerous bibliographic references related to the area. It would have been helpful if a chapter(s) was introduced early in the volume which described basic immunological techniques so that the reader could follow these more accurately in subsequent chapters on individual tumor antibodies. In addition, it was very difficult for the uninformed reader to grasp all of the nomenclature for the various antigens and antibodies since abbreviations were frequently used. I would recommend the text as a reference for any medical scientist who is interested in an overview of monoclonal antibodies techniques. However, this is not a text which can be used for instructional purposes in a n academic course. Iris H. Hall Division of Medicinal Chemistry and Natural Products School of Pharmacy University of North Carolina Chapel Hill, NC 27514
Environmental Chemistry, vol. 3. A Specialist Periodical Report. ti.J. M. Bowen, Senior Reporter.The Royal Society of Chemistry, London, U.K. 1984. 114 + ix pp. 14.5 x 22 cm. ISBN 0-85186-775-8. $74.00.
This volume reviews the literature published up to the end of 1982 and is made up of four chapters dealing with tropospheric ozone, organotin compounds, heavy metals in sewage sludge, and inorganic deposits in invertebrate tissues. Chapter 1 (I. Colbeck and R. M. Harrison) reviews the