THE MOUNT SINAI MEDICAL CENTER (Ne GUSTAVE L. LEVY PLACE » NEX YORK, NAL 19929 iene raed Mount Sinai School of Medicine > The Mount Sinai Hospical Department of Neoplastic Diseases July 5th » 1979 Radiumnemmet Karolinska Hospital S-104-01 Stockholm 60 Sweden ; l am privileged to have the opportunity to discuss with you the possibitity of recognition for major contributions to chemotherapy, and to do so in a confidential manner, since my secretary who is typing this is absolutely trust- worthy and discreet. , There ara many men who have made contributions to chemotherapy of great importance, George Hitchings synthesized 6-mercaptopurine, thioguanine, imuran, daraprim and discovered the significance of differential binding to the folic acid related enzymes which has allowed for treatment of toxoplasma, pneumocystis and bacterial diseasas, He also led the team that synthesized allopurinol. His co- worker In much of this activity was Gertrude B. Elion. Surely, Hitchings in terms of his contributions to human welfare must be high on anyone's list. : ’ iF one looks at chemists in the cancer chemotherapy area after Hutchings, Heidelberger's synthesis of 5-fluorouracil, 5-trifluorpmathyldeoxyuridine (trifluorothymidine) and his work in the chemistry of carcinogenesis merits recognition, Umezawa, In Japan, has been the prime chemist associated with antibltotic dayvelopmant for cancer, and aside from anthraycyclines has dominated the fie] Among those who on experimental levels mada the telling contribution to chemotherapy of neoplastic disease, one must mention Lloyd Law, who isolated the L-1219 tumor, parformed tha first Luria-Pelbruck experimant on the origina of resistance jn tumor cells, and first undertook combination chemotherapy with aninopterin and azaguanine, Abraham Goldin tenaciously demonstrated the characteristic of the complex pharmacology of anticancer drug and the tumor, in a legion of critical studies on how to use the ‘antifols in leukemia. His research is the most complete treatise on the pharm logy of an anticancer drug extending over twenty-five years, Seek oF Howard Skipper and Frank Schabel revolutionzed the concepts of chemotherapy r- cure, laying stress on residual cells and the necessity for treating them, Their work has profound influence on clinical chemotherapy and in a systematic corpus has underlay some of the clinical. events which have occurred. fo i -~ Page 2 - We 2ration also for the significance of his work sncubag th PR rencs PmMoact of several cancer drugs on tumor end normal cells, using the clonal coir unit technique For normal and tumor cells. asked about clinical candidates. 1 doubt that there are clinicians whose mantis have the sare _mpor tance that Hi tchings or Law have contrioutead, aa aaa j give Be sk ASSassmeanl wht moderate raiuciasc ere Foous . ron & moet REPL ee as contenders, | believe, would ba Frei, Fraireich, Frei succeaded me at the Cancer Institute and chatred with me the organization of the first study of combination chamotherapy in childhood acute leukemia. He and Freireich undertook the first multi-combination chemotherapy, VAMP, in acute lymphocytic Teukemia and he organized the trial of combination chemotherapy of Hedgkin's disease. He postulated the first successful treatment for Burkitt's tumor using Skinperian techniques, and has generally had a pervasive influence on American cancer research, Freireich conducted the first trial proving the activity of a drug during remission of acute leukemia in a study of 6-mercaptopurine by the Acute Leukemia Group 5, and is the senior author of the VAMP multidrug partially curative regimen in acute lymohocytic leukemia, Burchenal is one of the earliest students of acute lymphocytic leukemia and with Karnofsky, now deceased, Inaugurated much of the early research in alkylating agents in bread scale application. He introduced 6-mercaptopurine to clinical practice, He was contemscraneous with Law in demonstrating the effect of combination cnemotherapy in mouse tumors, Koliand initiated the first trial of combination chemotherapy in acute lymphocytic leukemia, which became the substance of the work which he and Frei published. Ha demonstrated the effect of intensive courses of chemotherapy on acute — myelocytic leukemia for induction and demonstrated with Bekesi successful immuno- therapy of acute myelocytic leukemias. He recognized the effects of adriamycin on osteosarcoma and conducted a successful surgical adjuvant trial with it. He intro aise platinum for the treatment of testicular tumors, and demonstrated the curability o ovarian cancer with adriamycin and platinum. ically asked about Hertz and the antifol treatment of trophodlast ic t was conducting clinical pharmacological studies with methotrexate Cancer Institute, extrapolating some of Goldin's pharmacology hi . gh-dose intermittant methotrexate, Pattents with trophoblastic ying on Hertz's service without specific therapeutic plans and were ticipate in this clinical pharmacologic trial, M,C. Li recognized gonadotropin levels, and interrupted the pharmacologic trial to convert utic one. The original report was Li, Hertz, and Spencer, and shartly association with the project was terminated. Hertz and his colleagues - ‘ine the optimal treatment approaches. Since the Initial observations ot purposerul and were not made by Hertz, | have always had some reservations about its prizeworthiness. | have been disturbed by Li's sometime exclusion from the recognition that has already accrued. Hertz and his collaborators did systematically introduce orthparpr ime dichlorodiphenvt, dichloroethane (0, P' ppd) for the treatment of adrenal carcinoma, which is a.notable accomplishment. » Pings} datraduced cranial radiation for the trestment of acute lymenocytic Jan ifs Seles tot ad } therapy regimens for acute Lympnoc cytic laukeata c theraby inferior, presumably From imevine- 3 by the Acute Louk stia Group B and many other ie conducted a controlled trial comparing this pi » be 7 tall his prior research had been conducted with a trsaiment regimen. For the greater part of his investigation approuriate e¢ were not used, and now there is substantial fallout of. cerebral abnore sli- . 2 rotkly associated with cranial radiation, ‘The costs of this must De & chad zy ig°S wiOse research designs were more approgriate. Pinkel aiso faan f-2 cessation of maintenance £; reatment in acute lymphocytic leukemia at thre @ years without controls, thus incurrin ng a 20% failure rate (and death). | have never considered Pinkel's research designs to be elegant, or even acceptable. The least ons can say is that he and his colleagues publish a lot. Pinkel did innovate g therapeutic approach.to embryonal] rhabdomyosarcoma integrating chemotherapy, radiation and surgery which is of high quality. He also initiated the use of cancer drugs on a surface area basis, derived from the pediatric practice for Fluids and calories. David Galton of Great Britain introduced many of the alkylating agents that are still in use today, chlorambucil, busulfan and melphalan emong them, and has been an influential, meticulous worker his entire life. The corpus of his work deserves consideration. Two additional names in cancer research that merit "your cons!deration } believe e are McCullough from Toronto whose technique of identification of colony Forming . units has had major impact on quantitative biology. Lest, but by no means least, is the serlous omission, | belleve, of recogni tio for Ludaik Gross, whose ploneering iconoclastic studies on viral etiology of murine leuxesia provided impetus for a major segment of the world's research fn neoplastic diseases, Aside from Joseph Beard who worked in avian leukosis, the concept of viral etiology of cancer had nearly died out when Gross made his observations on the Gross virus. From his research also came the Polyom§ virus. he importance of these cbservations has not yet run out. There is still a possibility that a Cmp.ccvicle of the Gross virustwill be shown to impart viral sequefces to DNA which are important in their inter action with environmental stimuli to produce cancer, Furthermors, amonstrated the potential for immune prophylaxis against cancer in his No rejected carcinogen induced sarcomas. His contribution’to cancer reasearch in two major spheres are, } balieve, reminiscent of cha in recounttion which characterized the prize for Peyton Rous. d C34 ant 5 i Gross a al fuadarants Y long deia Tne candidates are many and | believe you would not go wrong to pick among, the ist J scientists. still am not certain in my own mind after dictating this. letter that Ciiniciass hava yat earned a place on the same honor roll. With every gond wisn, Sincerely, a ia Oecati JFH Sib , James F. Holland, M.b. Professor and Chairman “UO uv? ? rooms, merrow ( i apy jm acute leukemis raay a 1 cot ee : e 7 ee ee as ne rapt he yee Tae ek egy BVO Org pave wim -ercute - i ad a a aor be 2 f via se oo leukemia, AT] of these have been foundations oa which subsequent | workers have built, but all were undertaken when the sledding was the hardest. ao P.P.S. Delayed submission. On further reflection, Dr. Bernard Fisher is an additional candidate who merits consideration. Fisher with his brother, Edwin Fisher, undertook a long series of experiments in the sixties relating to transplantability of tumors. Bernard Fisher analyzed the first trial of adjuvant chemotherapy in breast cancer performed with Thiotepa, and although essentially negative in its impact, Fisher gleaned important information from it, and continued with the National Surgical Adjuvant Breast Program, evolving a one, and then two, and then three drug adjuvant chemo- ‘therapy for breast cancer. Although none of these chemotherapies per se appears to be the best now available, the scope, quality, and impact of his studies on the practice of surgery in breast cancer is prizeworthy. Harry Eagle merits consideration on two grounds. His studies on the kinetics of bacterial growth undergoing penicillin treatment was a fundamental treatise in the forties. His systematic delineation of the nutritional requirements of mammalian cells in vitro was a major accomplishment allowing studies of nutritional and drug mechanisms of action to be conducted in chemical terms.