A small manufacturing defect, known but rarely noted, occurs at approximately every 34th row of each of the chips of WFPC2. This defect induces errors in photometry at the 0.01–0.02 mag level for ...about 6% of all stars, and periodic errors in astrometry for all stars, with an amplitude of 0.03 pixel. We derive simple corrections for these errors. The errors exist in all astrometry and photometry previously done with WFPC2, but they can be avoided in future work by applying the corrections that we give here.
Triapine is a potent inhibitor of ribonucleotide reductase (RNR), which is required for the conversion of ribonucleotides to deoxyribonucleotides. Two phase I trials in patients with hematologic ...malignancies demonstrated that Triapine could reduce circulating blasts in the majority of patients without significant non-hematologic toxicity (Giles et al. Leuk Res 2003; 27:1077–1083; Karp et al. Blood 2002; 100:560a). Preclinical studies have shown that the combination of Triapine and ara-C produces additive or synergistic cytotoxicity against several tumor cell lines, potentially by increasing intracellular ara-CTP levels when Triapine inhibits RNR. Therefore, a phase I study of Triapine in combination with ara-C was conducted in 32 patients with relapsed or refractory acute leukemia and high-risk MDS (1 MDS, 28 AML, 2 Ph+ ALL, and 1 Ph- ALL) in order to determine the tolerability, safety, and maximum tolerated dose (MTD). Triapine® was administered at a dose of 105 mg/m2/d as a 6-hour infusion for 5 consecutive days (D1–5) followed immediately by ara-C 100 (n=4), 200 (n=6), 400 (n=7), or 800 (n=8) mg/m2/d as an 18-hour infusion for 5 consecutive days (D1–5). Median age was 59 years (range, 15–83 years). Median ECOG status 1 (range, 0–2). Median number of prior therapies was 2 (range 1–9), including prior autologous (n= 2) and allogeneic stem cell transplant (SCT) (n=4). Dose-limiting toxicities (DLTs) were observed at the 800 mg/m2 ara-C dose level (1 patient each with grade 4 mucositis; grade 4 neutropenic colitis, sepsis and death; grade 4 neuropathy; and grade 4 hyperbilirubinemia). Therefore, the study was amended to include an ara-C dose level of 600 mg/m2/d. Seven patients were treated at this dose level without development DLTs. Thirty-one patients received at least 1 course, 2 received 2 courses, and 4 received 3 courses; 1 patient withdrew prior to completion of 1 course of therapy. Of the 31 evaluable patients, 4 (13%) patients (3 AML, 1 Ph+ ALL) achieved a CR (1 at an ara-C dose of 800 mg/m2; 2 at 600 mg/m2; 1 at 200 mg/m2). Two of the responders also achieved a complete cytogenetic remission (including 1 Ph+ ALL). All responses occurred after 1 induction course. One patient went on to receive an allogeneic (SCT) and continues in CR. Duration of responses was 9, 20, 52+, and 73+ weeks. Mean Cmax and AUC achieved for Triapine were 1.13 μg/mL and 251.5 min•μg/mL. The most frequent toxicities included nausea &/or vomiting (66%), elevated liver enzymes (50%; gr. 3 in 22%), fever (47%), diarrhea (41%; gr. 3 in 6%), rash (31%; gr. 3 in 6%), mucositis (28%), hand-foot syndrome (16%; gr. 3 in 3%), and peripheral edema (16%; gr. 3 in 9%). Triapine and cytarabine has activity in patients with relapsed or refractory acute leukemias. The recommended phase II dose is Triapine 105 mg/m2/day for 5 consecutive days (D1–5) followed by ara-C 600 mg/m2/d for 5 consecutive days (D1–5).
Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure−activity relationship (SAR) study of compounds arising from substitution at the 3-position ...of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.
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