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Pemetrexed disodium (ALIMTA ® , "pemetrexed") is a novel, multi-targeted antifolate that has demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung, breast, mesothelioma, colorectal, pancreatic, gastric, bladder, cervix, and head and neck. Pemetrexed inhibits multiple folate-dependent enzymes involved in both purine and pyrimidine synthesis including thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase. As a single agent, pemetrexed exhibits a moderate toxicity profile at a dose of 500 mg/m 2 by 10-minute infusion once every 21 days with myelosuppression being the dose-limiting toxicity. Folic acid added to the diet in preclinical studies reduced toxicities while maintaining antitumor activity. Based on this observation and clinical toxicities, folic acid and vitamin B 12 dietary supplementation has been recently introduced into all ongoing trials. Studies combining pemetrexed with other active chemotherapeutic agents demonstrate that these combination therapies may become important treatment regimens in a variety of cancer types. Currently, pemetrexed phase III trials are ongoing in mesothelioma and non-small cell lung cancer with future trials planned to explore this unique multitargeted antifolate.

Budotitane [cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)] is a novel inorganic metal complex. Preclinical studies in established screening models indicate considerable antitumor activity. We have performed a clinical Phase I and pharmacokinetic trial with budotitane administered as i.v. infusion twice weekly. The starting dose of 100 mg/m2 was derived from a prior single dose Phase I study. Eighteen patients with solid tumors refractory to all other known treatment modalities were entered. 17 patients had received prior chemotherapy. Dose levels ranged from 100 mg/m2 to 230 mg/m2, with a total of 122 budotitane infusions administered. Neither leuko- nor thrombocytopenia were observed. 2/5 pts at 180 mg/m2 and 2/4 pts at 230 mg/m2 developed a 3-fold increase of reticulocytes without signs of hemolysis or bleeding. Nonhematologic toxicity was moderate at doses of < or = 180 mg/m2. Fifteen patients reported loss of taste at the day of infusion. At 230 mg/m2, 2/4 pts developed WHO grade 3 cardiac arrhythmias with polytope premature ventricular beats and nonsustained ventricular tachycardia. A limited pharmacokinetic analysis was performed at dose levels 180 mg/m2 and 230 mg/m2. At 180 mg/m2, Cmax was 2.9 +/- 1.2 microg/ml, t1/2 78.7 +/- 24.4 h, Cltot 25.3 +/- 4.6 ml/min and AUC 203 +/- 71.5 h x microg/ml. At 230 mg/m2, Cmax was 2.2 +/- 0.8 microg/ml, t1/2 59.3 +/- 12.1 h, Cltot 44.9 +/- 23.6 ml/min and AUC was 183 +/- 90.4 h x microg/ml. No objective tumor response was observed. We conclude that the maximum tolerated dose of budotitane administered twice weekly is 230 mg/m2, the dose limiting toxicity is cardiac arrhythmia. Further evaluation of the nature of the cardiac toxicities observed is warranted. Using this schedule, 180 mg/m2 is a safe dose for subsequent clinical studies.

Docetaxel is an active drug in patients with advanced squamous cell carcinoma of the head and neck.

S phase entry, I.e. start of DNA replication, Is a crucial step in proliferation. Inhibition of S phase entry correlates with Inbibition of hypusine formation, an event affecting only the eukaryotie Initiation factor $A (elF4A), Its hypuslnecontalning sequence wus postulated to authorize polysomal utilization of specific trauscripts for proteins necessary to enable DNA replication. Using ndmodne to reversibly suppress the hyposinc-forming deoxyhypusyi hydmxylase (E.C. 1.1¢99.29) in cells while differentially displaying their polysomal versus non-polysemal mRNA popolations, we report the detection and cla~!fleation of several mRNA species that indeed disappear from and reappear at !lo1-ysomes in con~rt with inhibition and d_!s!nhibition, respectively, of hypusine formation. Based on initial sequence data, two trauslationally controlled enzymes, both critical for proliferation, are identified us candicate wodncts of such mRNAs, methionine adenosyitrausferuse (E.C 2.$.1.6) and cytochrome-c oxiduse 0gC 1.9.3.1) subunit 1. The existence of such potative hyposinedependent messenger nnclde adds (/O, mas) prevides the basis for a proposal on their molecular function in onset of multiplication.Key words: Post-translational modification; eIF-5A; Hypusine; Cell cycle control; Translational control; mRNA I, IntroductionThe unique amino acid hypusine [~-(4-amino-2(R).hydroxybutyl)-t.-lysine] is formed post-translationally by the sequential action of deoxyhypusyl synthase (DOHS) and deoxyhypusyl hydroxylase (DOHH) on a single lysyl residue in only one cellular protein, the eukaryotic initiation factor 5A (elF-SA) [I-3]. The hypusine-containing domain shows remarkable interspecies conservation, and a sequence of 12 amino acids containing the hypusine residue has been strictly conserved throughout eukaryotic evolution, from fungi to plants, insects, and mammals [3]. Hypusine formation, which has not been demonstrated in prokaryotes [2], is an absolute requirement for growth of $. cerevesiae [4], and a number of *Correspondin8 authors, Fax: (I) (212) 746 0300 and Fax: (I) (212) 746 6382, respectively.'For Stephen Biko (December 18, 1944.-September 12, 1977.reports have established correlations between hypusine formation and the proliferation of eukaryotic cells (see [2,3]). However, the exact physiological function of this presumed translation initiatic~n factor is unknown, and at present it even is unclear whether elF-SA functions at the pretranslational and/ or the translational level [3].Deoxyhypusyl hydroxylase (E.C. 1.14.99.29), which catalyses the final step of hypusine biosynthesis, is apparently related [5,6] to other protein hydroxy]ating enzymes such as prolyl 4-hydroxylase (E.C 1.14.11.2) [7] and is effectively inhibited by mimosine (3-(N-(3-hydroxypyridin-4-one))-2[S]-aminopropionic acid), both in vitro and in culture [3]. This coincides with proliferative arrest in the late GI phase ofthe cell cycle [3,[8][9][10][11]. Fast recovery ofcellular DOHH activity occurs upon mimo,,;ine removal, an effect parallele...

The combination of MTA and cisplatin is clinically active, and administering both agents on day 1 is superior to a split schedule. Further development of this combination for mesothelioma is warranted.

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