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The reactions of [Pt(dpma)(H 2 O) 2 ] 2+ (dpma = 2,2'dipyridylmethylamine) and [Pt(dpk)(H 2 O) 2 ] 2+ (dpk = 2,2'-dipyridylketone) with the model nucleobases 1-methylthymine (1-MeT) and 1-methyluracil (1-MeU) were studied. Reaction products were characterized by 195 Pt NMR spectroscopy and by X-ray structure analysis. The symmetric dpma and dpk diaqua complexes form dinuclear complexes with 1-methylthymine, acting as secondary bridging ligand via its N3 and O4 donor atoms. [Pt 2 (dpma) 2 (1-MeT) 2 ](ClO 4 ) 2H 2 O (5) and [Pt 2 (dpk)(dpk´H 2 O)(1-MeT) 2 ](PF 6 ) 2´4 H 2 O (6) both show a head-to-head arrangement. Biological tests show a significant in vitro antitumor activity of [Pt(dpk)Cl 2 ] against the human glioma cell line U 87. Platin(II)-Komplexe mit Dipyridyl-Ligandsystemen und ihre Produkte mit den Modell-Nukleobasen 1-Methylthymin und 1-Methyluracil Inhaltsu È bersicht. Die Reaktionen von [Pt(dpma)(H 2 O) 2 ] 2+ (dpma = 2,2'-Dipyridylmethylamin) und [Pt(dpk)(H 2 O) 2 ] 2+ (dpk = 2,2'-Dipyridylketon) mit den Modell-Nukleobasen 1-Methylthymin und 1-Methyluracil wurden untersucht und die Reaktionsprodukte 195 Pt-NMR-spektroskopisch und ro È ntgenstrukturanalytisch charakterisiert. Die symmetrischen Diaquakomplexe der Ligandsysteme dpma und dpk bilden dinukleare Komplexe mit 1-Methylthymin. Die Modellnukleobase fungiert als zweiter verbru È ckender Ligand u È ber die N3-und O4-Donoratome. [Pt 2 (dpma) 2 (1-MeT) 2 ]-(ClO 4 ) 2´H2 O (5) und [Pt 2 (dpk)(dpk´H 2 O)(1-MeT) 2 ]-(PF 6 ) 2´4 H 2 O (6) zeigen beide eine Kopf±Kopf-Anordnung bezu È glich der Modell-Nukleobase. In biologischen Tests weist der Komplex [Pt(dpk)Cl 2 ] eine signifikante in vitro Antitumoraktivita È t an der Zellinie U 87 auf.

Mesna, a reactive thiol, often encounters cisplatin and carboplatin in combination protocols involving oxazaphosphorines and platinum drugs. This co-administration might be unfavorable based on the inactivation of platinum drugs by thiol groups in vitro. We investigated whether mesna influences the pharmacokinetics of platinum drugs when co-administered with cisplatin or carboplatin. The pharmacokinetics of platinum drugs were investigated in 18 pediatric patients receiving either cisplatin or carboplatin in a combination with or without mesna. In cisplatin patients, a decrease in the distribution clearance of total platinum was observed when mesna was co-administered (CLd, 2.2 +/- 0.1 mL/min.kg; n = 3), compared to cisplatin without mesna (CLd, 4.8 +/- 1.5 mL/min.kg; n = 5) (p = 0.029, t-test). This might have been caused by an influence of mesna in slowing down the protein binding of cisplatin since a trend (p = 0.057) in prolonged distribution half-life of total platinum was also observed when mesna was present (t(1/2a) 65 +/- 21 min; n = 3) compared to cisplatin without mesna (t(1/2a), 32 +/- 18 min; n = 5). However, the impact of these changes on the area under the concentration time curve (AUC), total clearance (CLt), and volume of distribution (V) for total platinum and ultrafilterable platinum species was hardly noticeable. In carboplatin patients, when mesna was co-administered: AUC (2.5 +/- 0.4 mg.min/mL.400 mg/m2; n = 5) CLt, (6.8 +/- 5.1 mL/min.kg; n = 6), and V (0.7 +/- 0.4 L/kg; n = 6) for ultrafilterable platinum species were not significantly different from when carboplatin were administered without mesna: AUC (2.3 +/- 1.3 mg.min/mL.400 mg/m2; n = 4), CLt (5.8 +/- 4.6 mL/min.kg; n = 5), and V (1.1 +/- 1.1 L/kg; n = 5). Hence, mesna does not significantly influence the pharmacokinetics of cisplatin and carboplatin in pediatric cancer patients.

Duchenne muscular dystrophy (DMD) gene transcripts are most abundant in normal skeletal and cardiac muscle and accumulate as normal myoblasts differentiate into multinucleated myotubes. In this report we describe our initial studies aimed at defining the cis-acting sequences and trans-acting factors involved in the myogenic regulation of DMD gene transcription. A cosmid clone containing the first exon of the DMD gene has been isolated, and sequences lying upstream of exon 1 were analyzed for homologies to other muscle-specific gene promoters and for their ability to direct muscle-specific transcription of chimeric chloramphenicol acetyltransferase (CAT) gene constructs. The results indicate that the transcriptional start site for this gene lies 37 base pairs (bp) upstream of the 5' end of the published cDNA sequence and that 850 bp of upstream sequence can direct CAT gene expression in a muscle-specific manner. Sequence analysis indicates that in addition to an ATA and GC box, this region contains domains that have been implicated in the regulation of other muscle-specific genes: a CArG box at -91 bp; myocyte-specific enhancer-binding nuclear factor 1 binding site homologies at -58, -535, and -583 bp; and a muscle-CAAT consensus sequence at -394 bp relative to the cap site. Our observation that only 149 bp of upstream sequence is required for muscle-specific expression of a chimeric CAT gene construct further implicates the CArG and myocyte-specific enhancer-binding nuclear factor 1 binding homologies as important domains in the regulation of this gene. On the other hand, the unique profile of myogenic cell line-specific induction displayed by our DMD promoter-CAT gene constructs suggests that other as yet undefined cis-acting sequences and/or trans-acting factors may also be involved.