First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies.

Purpose: Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models.

Methods: This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11).

Bis-benzimidazole anticancer agents: targeting human tumour helicases.

Certain DNA minor groove binding agents, distamycin, netropsin, and a series of anticancer bis-benzimidazoles can block DNA helicase activity by binding to duplex DNA at specific base sequences. DNA helicases are crucial to cell DNA replication, transcription and repair because these enzymes separate double-stranded DNA, thereby preparing the strands for enzymatic manipulation. From our studies we have developed a hypothesis that focuses on cellular DNA helicase action as a mechanistic site where these minor groove binders can act.

Enediyne-lexitropsin DNA-targeted anticancer agents. Physicochemical and cytotoxic properties in human neoplastic cells in vitro, and intracellular distribution.

Two series of hybrids of a dynemicin A model and DNA minor groove binding lexitropsins were synthesized and their cytotoxic activities were investigated in a panel of human normal and malignant cell lines using a colorimetric assay. Adriamycin was used as a control. Several of the agents demonstrated cytotoxic activity, the extent of which varied with tumor type.

Late outcome and quality of life after complicated heart operations.

Background: Patients with severe postoperative complications consume a great deal of the economic resources for intensive care. Our knowledge of the late outcome and quality of life of these patients is scarce.

Methods: One thousand five hundred twenty-two patients undergoing cardiac operations during 1991 and 1992 were studied, and the 100 patients who needed the most expensive treatment were identified.

Influence of nucleic acid base aromaticity on substrate reactivity with enzymes acting on single-stranded DNA.

Stacking between aromatic amino acids and nucleic acid bases may play an important role in the interaction of enzymes with nucleic acid substrates. In such circumstances, disruption of base aromaticity would be expected to decrease enzyme activity on the modified substrates. We have examined the requirement for DNA base aromaticity of five enzymes that act on single-stranded DNA, T4 polynucleotide kinase, nucleases P1 and S1, and snake venom and calf spleen phosphodiesterases, by comparing their kinetics of reaction with a series of dinucleoside monophosphates containing thymidine or a ring-saturated derivative.

Influence of intrathecal morphine and naloxone intervention on postoperative ventilatory regulation in elderly patients.

Thirty elderly patients undergoing major hip surgery under spinal analgesia were randomly allocated in a double-blind manner into three groups. The aim was to evaluate the influence of intrathecal morphine and postoperative naloxone infusion on the regulation of ventilation. The Bupivacaine Group received spinal analgesia with 20 mg bupivacaine intrathecally.

Nuclear magnetic resonance spectroscopy and sensitizer-adduct measurements of photodynamic therapy-induced ischemia in solid tumors.

Dunning R3327-AT prostate carcinomas growing in Fischer X Copenhagen rats were treated with interstitial photodynamic therapy (PDT--15 mg/kg Photofrin II 4 hours before illumination with 630-nm light via four parallelly implanted optical fibers) at different light intensities. Forty to 60 minutes after treatment, 31P-nuclear magnetic resonance spectra of tumors in anesthetized animals were obtained at 2.35 Tesla using surface coil localization.

32P-postlabeling detection of radiation-induced DNA damage: identification and estimation of thymine glycols and phosphoglycolate termini.

A 32-P-postlabeling assay has been developed that permits detection of several radiogenic base and sugar lesions of DNA at the femtomole level. The technique is based on the inability of DNase I and snake venom phosphodiesterase to cleave the internucleotide phosphodiester bond immediately 5' to the site of damage so that complete digestion of irradiated DNA with these nucleases and alkaline phosphatase yields lesion-bearing "dinucleoside" monophosphates. Because these fragments contain an unmodified nucleoside at the 5'-end of each molecule, they can be readily phosphorylated by T4 polynucleotide kinase and [gamma-32P]ATP and analyzed by polyacrylamide gel electrophoresis and reverse-phase HPLC.

Metabolic binding of misonidazole to mouse tissues. Comparison between labels on the ring and side chain, and the production of tritiated water.

The 2-nitroimidazole, misonidazole, is of current interest as an imaging agent for hypoxic regions in tumors and in vascular disease such as stroke. The basis of this technique is the reductive activation and binding of nitroheterocycles which is much more efficient in the absence of oxygen. The appropriate molecular location for an active isotope on the nitroheterocyclic probe depends on the nature of the metabolites retained in tissues after the parent drug has been cleared.