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I @ Folateantagonistsalsoillustrated;Inadditiontobaker's [CANCER RESEARCH 39, 293-304, February 1979] 0008-5472/79/0039-0000$02.00 Toward Improved Selectivity in Cancer Chemotherapy: The Richard and Hinda Rosenthal Foundation Award Lecture1 Joseph R. Bertlno2 Yale University School of Medicine, New Haven, Connecticut 06510 dylate synthetase per se or as facilitators of 5-fluorodeox yuridine 5'-monophosphate binding to this enzyme are also discussed. The potential for selectivity using nonclassical @ I folateantagonistsisalsoillustrated;inadditiontoBaker's antifol (triazinate), a triazine folate antagonist, now in clinical trial, several 2,4-diaminoquinazolines were found to be potent exhibitors of DNA synthesis in human leukemic leukocytes. Drug resistance to antineoplastic agents continues to be an important clinical problem. By using resistanceto meth otrexate as an example, exploitation of drug-resistant mu tants by design of specific inhibitors is possible. A strategy h for the prevention of drug resistance is advanced, based on F dataderivedfromexperimentalsystems.Itisconcluded —@-@ that large doses of drugs used in intermittent fashion and @1 sequentially in combination may be the best strategy to avoid this problem. An example of this strategy is Adriamy cin-cyclophosphamide-Oncovin-methotrexate-1 -f3-D-arabi nofuranosylcytosine, a five-drug sequential combination used to treat diffuse histiocytic lymphoma. Dr. Miller, Mr. and Mrs. Rosenthal, members and guests of the American Association for Cancer Research, I am deeply honored to receive the Rosenthal Award. I have been extremely fortunate over the years I have been at Yale to have many outstanding colleagues, fellows, I and graduate students, and they havereally been responsi ble for whatever success we have had. I had prepared a list of their names to show you but decided not to; it might embarrass those who wish not to admit an association, and it was embarrassing to me to realize I have accomplished so little with so much talent. I will acknowledge their respective contributions during the course of this lecture. Abstract The history of chemotherapy has not been characterized by smooth sailing. There have been many Bermuda trian Approaches to improving the selectivity of drugs for the gles along the way, and the success achieved has surprised treatment of patients with cancer are discussed, with em many scientists who doubted that progress was possible phasis on folate antagonists as prototype compounds. The with the deficiencies in our basic knowledge of the neoplas useof metabolites (leucovorin, 5-methyltetrahydrofolate)as tic process. What will the role of chemotherapy be in the “rescue' ‘ agents following methotrexate treatment with next decade? I was going to indicate in Table 1 that the appropriate monitoring of blood levels of methotrexate has 1980's would establish chemotherapy as an alternative to led to the safe use of this antimetabolite in high doses and surgery or radiation therapy for the treatment of some an improved therapeutic index for the use of this drug in human cancers, but since some of my best friends are some human cancers. The use of methotrexate in conjunc surgeons and radiation therapists, I decided not to strain tion with fluorouracil administration is sequence dependent our relationships. in experimental tumor models and is being tested in human I had the good fortune to have Frank Huennekens and tumors. New folate antagonists, designed to inhibit thymi Clem Finch as my mentors while a postdoctoral fellow quite a few years ago, and then to work with Arnold Welch and I Presented at the 1978 Meeting of the American Association for Cancer the “gangoffour―(Dr.Evangelo Canellakis, Dr. Robert Research in Washington, D. C. Supported in part by Grants CAO8O1Oand Handschumacher, Dr. William Prusoff, and Dr. Alan C. CA08341 and Contract NO-1-CM-33711. 2 American Cancer Society Professor of Medicine and Pharmacology. Sartorelli) at Yale for several more years; therefore it's Received October 16, 1978; accepted October 26, 1978. probably not surprising that my approach to chemotherapy FEBRUARY 1979 293 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1979 American Association for Cancer Research. J. R. Bertino Table 1 MIX@ Historyof chemotherapy:the pessimist'sview 1940's Chemotherapycan't work—wedon't understandthe dif @,MTX(G)N ferencebetweennormal and cancercells. @MTX@ @ ‘ Purines(C2,C1) 1950's Chemotherapyis effective, but patientsalwaysrelapse. DHFRMTx(G)N 1960's Chemotherapy can cure choriocarcinoma and Burkitt's FH2(G).@- u.FH4(G)N― lymphoma,but theseare unusualtumors. 1970's Chemotherapycancure severaltumors, but the drugs are @ dTMP FH4(G @N too toxic, i.e., lack selectivity. ‘I 1980's ? DNA dUMP Eztrocslhilor TT@ Compartment Cell Membrane Chart 1. Mechanism of MTx action and folate metabolism. 5CH3FH4, has been to try to understand why drugs work or don't MeFH4;5-CHOFH4, leucovorin. work. The following quote from GeorgeHitchings, who has done this as well as anyone fairly well summarizes this especially in the presence of NADPH and at a slightly acidic approach (64). pH (15). Under these conditions, the binding is one to one and has been referred to by the late Dr. William Werkheiser , ‘Historically most chernotherapeutic agents have been used without an understandingof their mechanismsof action. However, as “stoichiometric―(111,112). the potential rewardsof such understandingareenormous,for the Since thymidylate synthetase action, rather than FH4 practical application of the drug, the discovery of more selective formation via DHFR activity, is rate limiting, only when agents,and for fundamentalknowledge.― DHFR is completely inhibited and when excess or “free― MTX is present in the cell, as emphasized by Goldman, With that preamble, I would like to review for you some of Sirotnak, and coworkers, does FH4 synthesis stop and, our studies and indicate the approaches we are taking in consequently, thymidylate biosynthesis (32, 52, 100). Cells our current research. rapidly synthesizing DNA will of course be depleted of FR, During the past 20 years, a relatively complete description most rapidly. Since FR, is also required for purine synthe of how one clinically useful drug, MTX,3 exerts its effects sis, purine deficiency may also occur; as shown by Hryniuk on cells has become available. I would like to review this et a!. (66), this may be an important mechanism of cell information briefly for those who are not working in this death in some cell types. field (Chart 1). Therefore, some of the factors that relate to cell death In order to prevent a cell from replicating, MTX must first due to MTX are the level of excess or free MTX in cells, the cross the cell membrane. Work from several laboratories rate of dissociation of MTX from the inhibited enzyme when has shown that MTX uptake is an active process and that intracellular levels decrease as a function of decreasing this drug enters cells predominantly by utilizing the carrier extracellular levels, the rate of synthesis of DNA, and the system responsible for transport of reduced folates (10, 11, rate of synthesis of the target enzyme DHFR (9, 19, 21, 65, 17, 39, 50, 51, 53, 56, 67, 85, 99). Since MTX competes 104). effectively with the naturally occurring folates for uptake, it In recent years, as a result of studies in several laborato follows that high extracellular concentrations of this drug ries, it has become clear that the folate coenzymes in cells will inhibit uptake of MeFH4, the predominant form of folate exist as polyglutamates and that these compounds, rather in plasma. Thus an additional site of action of MTX, espe than being inactive storage forms, are the natural cofactors cially as used in the high-dose regimens, may be to starve for one-carbon enzyme reactions (33, 34). Recent studies cells of reduced folates. When extracellular concentrations have indicated some conversion of MTX to a diglutamate of MeFH4 or 5-formyltetrahydrofolate (leucovorin) are in form in vivo (8, 113) and in vitro (83). The consequences of creased by administration of these compounds, effective this conversion are not clear; however, this derivative is as inhibition of MTX transport may result. In addition, as potent an inhibitor of DHFR as is MTX (70). A mutant line of leucovorin enters the cell, because of countertransport, Chinese hamster ovary cells has recently been shown to be more MTX leaves the cell (85). Thus leucovorin may amelio unable to synthesize folate polyglutamates (80, 106). These rate MTX toxicity not only by providing cells with a reduced cells cannot survive without the addition of the end prod folate coenzyme, thus bypassing the MTX block, but also ucts of folate metabolism, namely, a purine and thymidine, by decreasing the intracellular concentration of MTX as a indicating that the formation of folate polyglutamates is result of these effects on its transport (51, 85). Obviously, essential for cell growth, perhaps because these forms are the higher the concentration of leucovorin relative to MTX, retained by the cell, while folate monoglutamates are not. the more important are these effects. Clearly, we need to learn a great deal more about folate Once inside the cell, MTX rapidly binds to the enzyme polyglutamate forms and cell regulation. DHFR. This binding, although reversible, is extremely tight, How can we use what information we have on folate metabolism to improve the selectivity of folate antagonist chemotherapy? Since stem cells from normal renewal tis 3 The abbreviations used are: MTX, methotrexate; MeFH4, 5-methyltetra hydrofolate; DHFR, dihydrofolate reductase; FH4, tetrahydrofolate; ALL, sues also utilize the same pathways to synthesize DNA as acute lymphatic leukemia; 5-FU, 5-fluorouracil; CNS, central nervous system; do tumor cells, how can we get selective antitumor effects? i.t., intrathecal; dThd, thymidine; CPG,, carboxypeptidase G, TZT, triazin The realization that MTX, like other antimetabolites, is a ate; FdUMP, fluorodeoxyuridine 5'-monophosphate; CH,FH4, 5,10- methylenetetrahydrofolate; FdUrd, fluorodeoxyuridine; cDNA, complemen schedule-dependent drug, i.e.
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