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Editorial |
Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine Cancer Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
Correspondence: I. David Goldman, M.D., Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine Cancer Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, 10461, USA. Telephone: 718-430-2302; Fax: 718-430-8550; e-mail: igoldman{at}aecom.yu.edu
On February 5, 2004, pemetrexed (Alimta®; Eli Lilly and Company; Indianapolis, IN) was registered by the U.S. Food and Drug Administration for the treatment of mesothelioma. Pemetrexed is the first new antifolate to be approved in the U.S. for the treatment of cancer since the introduction of the dihydrofolate reductase (DHFR) inhibitors, aminopterin and methotrexate (MTX), in the late 1940s [1]. Why has it taken so long? It has not been for want of trying!
Following the introduction of MTX, hundreds of analogues were synthesized in an attempt to identify a better drug. Critical end points for drug development were the ability of candidate agents to A) inhibit DHFR, and thereby deplete cellular folates and starve folate-cofactor-dependent reactions, and B) directly inhibit other folate-requiring enzymes in the synthesis of thymidylate and purines. The approach was unsuccessful until decades later when it was recognized that drug-sensitive tumors metabolize MTX to polyglutamate derivatives, as occurs for natural folates, a reaction mediated by the enzyme folylpolyglutamate synthetase (FPGS) [2]. The importance of this biotransformation was that A) these derivatives are retained, and build to high concentrations, within cells and B) they expand the spectrum of targets inhibited by MTX to enzymes required for thymidylate and purine synthesis. Hence, it was not only the enzyme inhibitory properties of the parent compound that were critical but, equally important was its capacity to form polyglutamate derivatives, and the properties of these derivatives [3]. This led to the development of a new generation of antifolates, such as raltitrexed (Tomudex®; AstraZeneca Pharmaceuticals; Wilmington, DE) and pemetrexed, that, as polyglutamates, directly inhibit tetrahydrofolate-cofactor-dependent enzymes [4–6].
Pemetrexed has been termed a "multitargeted" antifolate. Its higher polyglutamate derivatives are potent inhibitors of thymidylate synthase (TS), with inhibition constants (Ki’s) of ~1 nM; TS is its primary target. Pemetrexed polyglutamates are weaker inhibitors of GAR transformylase (GARFT), required for purine synthesis, with Ki’s ~50-fold higher [5, 6]. The mono- and polyglutamate derivatives of pemetrexed are comparable and very weak inhibitors of DHFR, one one-thousandth the potency of MTX, which is itself a competitive inhibitor of this enzyme [3]. DHFR is required to reduce the dihydrofolate to tetrahydrofolate, generated in the synthesis of thymidylate by TS; however, marked and rapid suppression of TS by pemetrexed obviates the need for DHFR. There is no evidence at this time that suppression of DHFR plays a significant role in the activity of this drug. It is clear that, in the range of the pemetrexed 50% growth inhibitory concentration (IC50) in many mammalian tumors in vitro, the effects of this agent can be prevented by the provision of thymidine alone, which circumvents inhibition of TS. But when the concentration of pemetrexed is increased to high levels, the addition of a purine is required to fully protect cells, consistent with an added block at the level of GARFT [5, 6]. Since current clinical regimens employ a pemetrexed dose of 500 mg/m2, at the high blood levels achieved both enzyme sites are likely to be suppressed [7]. However, the relative time course of this suppression is not clear, nor is the extent to which blood purines can meet tumor needs for this substrate when de novo synthesis is blocked. While, intuitively, it might be expected that suppression of two sites should be better than one, it is of interest that there are studies with MTX suggesting that, under some conditions, greater suppression of thymidylate relative to purine biosynthesis might actually enhance the activity of this agent [8].
There are unique properties of pemetrexed that distinguish it from other antifolates. For instance, beyond differences in targets, pemetrexed is a much better substrate for FPGS than MTX [9]. Raltitrexed and pemetrexed are comparable substrates for FPGS, and their polyglutamate derivates are comparable inhibitors of TS; but raltitrexed does not inhibit GARFT [4, 6]. From the standpoint of clinical efficacy, however, there are no direct comparisons between these agents. In the laboratory, it is clear that, in many different cells lines, resistance to pemetrexed due to increased levels of TS or impaired "uptake" is usually far less than the level of resistance to raltitrexed [10, 11]. There are some recent insights into why this is the case when resistance is due to impaired transport mediated by the major folate transporter, the reduced folate carrier (RFC). Formation of pemetrexed polyglutamates is inhibited at the level of FPGS by endogenous folates in tumor cells [12, 13]. When there is failure of transport, not only is pemetrexed delivery decreased, but there is impaired transport of reduced folates as well, such as the prevalent blood folate 5-methyltetrahydrofolate. This results in a contraction of cellular folate pools and relaxation of suppression of FPGS, leading to sustained formation of active pemetrexed polyglutamates [14]. The impact of cellular folates on raltitrexed polyglutamation is far less prominent [13]. In cells in which all RFC activity is lost, there can be complete preservation of pemetrexed activity and, in some cases, collateral sensitivity to this drug, under conditions in which marked resistance to raltitrexed and, to a lesser extent, MTX, persists [15].
Pemetrexed has favorable membrane transport properties. It has good affinity for RFC, somewhat greater than that of MTX. Pemetrexed has an affinity for folate receptors that is orders of magnitude higher than that of MTX [16]. However, in the presence of RFC, transport mediated by folate receptors is negligible, since the cycling rate of folate receptor-
is only one one-hundredth that of RFC [17]. Even when folate receptor- was highly overexpressed, there was only a threefold increase in pemetrexed activity [18]. Pemetrexed transport may be more concentrative than that of MTX [14], which favors the formation of polyglutamate derivates, although the basis for this difference is unclear. Pemetrexed also appears to be a favored substrate for other transport carriers not, as yet, identified at the molecular level. For instance, in HeLa cells there is an RFC-independent transport route with an affinity for pemetrexed (Kt ~ 15 µM) much higher than for other antifolates [15]. There is prominent folate transport activity with low pH optima in most solid tumors (which have acidic cores) with a very high affinity for pemetrexed (Kt ~ 45 nM) [19, 20]. These processes provide routes for the preferential delivery of pemetrexed to tumor cells and may compensate, at least in part, when transport via RFC is impaired.
Not only is pemetrexed activity against tumors highly dependent upon the level of cellular folate cofactors, the folate status of the host is an important determinant of toxicity. In folate-deficient tumor-bearing mice, the therapeutic window for this drug is very low and narrow, with substantial toxicity at higher doses. However, when animals are folate replete, the therapeutic window is very broad, much higher pemetrexed doses are tolerated, and efficacy is preserved [21]. Suboptimal folate, and perhaps B12, status, as reflected by elevated serum homocysteine levels, was identified as an important determinant of pemetrexed toxicity based upon a very careful initial analysis of the phase III mesothelioma study [22]. This led to the administration of folic acid, at a level somewhat greater than the minimum daily requirement, and vitamin B12 to patients receiving this agent, a regimen that has markedly decreased the incidence of pemetrexed toxicity [23].
The phase III trial of pemetrexed compared this drug in combination with cisplatin with cisplatin alone [23]. There was a substantial benefit in the pemetrexed arm in terms of response rate, survival, and time to progression, with impressive symptomatic and functional improvements. In another phase III trial, pemetrexed efficacy was comparable to that of docetaxel, but with significantly fewer side effects, in previously treated patients with non-small cell lung cancer [24]. This agent has activity in a variety of other solid tumors [25]. Now that the drug is approved, we will learn much more about its utility and how it can be used most effectively in multidrug regimens. However, once a drug is established in the clinics, and there is a general understanding of mechanisms of action and resistance, it is tempting not to continue basic investigations. But, it should be kept in mind that it required 4 decades to develop a clear understanding of the pharmacologic basis of MTX action, and there is currently only rudimentary information on pemetrexed. Much more basic information is needed on A) the mechanisms of action of, and cellular resistance to, pemetrexed; B) the role of GARFT suppression in drug efficacy and resistance; C) the role of transporters that mediate pemetrexed entry into and exit from tumor cells as determinants of efficacy and resistance; and D) conditions that optimize its effectiveness and synergy with other agents. These studies can provide the reagents and approaches that will allow a comprehensive characterization of human tumors in order to identify the subset of patients who are likely to respond to this agent.
Pemetrexed may not be as exotic as many new molecularly targeted agents and biologicals, but it appears to have a broad spectrum of activity—it is cytotoxic to tumors, yet minimally toxic to patients, it can be administered on an every-three-week basis; and it now provides the opportunity to add a new antimetabolite with a novel mechanism of action to multidrug therapeutic regimens.
REFERENCES
-mediated transport and reduced folate carrier-mediated transport in L1210 leukemia cells. J Biol Chem 1995;270:7842–7849.This article has been cited by other articles:
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  T. Li, Y.-H. Ling, I. D. Goldman, and R. Perez-Soler Schedule-Dependent Cytotoxic Synergism of Pemetrexed and Erlotinib in Human Non-Small Cell Lung Cancer Cells Clin. Cancer Res., June 1, 2007; 13(11): 3413 - 3422. [Abstract] [Full Text] [PDF]
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