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Biomedical subjects

C W Porter

Publications and source records attributed to C W Porter.

130 records · Page 8Linked to original sources
PubMedDate not supplied

Interference with polyamine biosynthesis and/or function by analogs of polyamines or methionine as a potential anticancer chemotherapeutic strategy.

The obvious goal in cancer chemotherapy is selectivity. Highly cytotoxic agents abound but their usefulness as anticancer agents extends only so far as their specificity for tumor cells and tissues. In this context, we have reviewed those aspects of polyamine and AdoMet metabolism and function which might contribute to their potential as target sites for chemotherapeutic intervention. Although largely untested to date and far from unequivocal, these various considerations seem to provide sufficient rationale for continued evaluation of the therapeutic potential of these sites. Polyamine analogs and methionine analogs designed to modulate polyamine biosynthesis directly or through AdoMet formation have been discussed as strategies to effect this goal and previous studies with similar analogs have been reviewed. Progress achieved thus far with analogs derived from our own laboratories provides novel insights into polyamine and AdoMet metabolism and/or function as well as new leads towards the design of more effective agents and drug combinations. More detailed reading of the biochemistry of polyamines in eukaryotes and prokaryotes is available in several very excellent current reviews (6-9, 77).

Antineoplastic Agents↗
PubMedDate not supplied

Urinary and erythrocyte polyamines during the evaluation of oral alpha-difluoromethylornithine in a phase I chemoprevention clinical trial.

Pharmacokinetics of alpha-difluoromethylornithine (DFMO) in plasma and polyamine levels in urine and erythrocytes (RBC) of subjects considered to be at a higher-than-normal risk for developing cancer and receiving DFMO in a phase I chemoprevention trial were monitored over a period of 6 months at DFMO doses ranging from 200 to 6400 mg/m2/day. DFMO pharmacokinetics was linear and attained an average peak plasma concentration of 58 micrograms/ml and an average area under the concentration x time curve from 0 to 6 h of 240 micrograms/ml.h at an administered dose of 1600 mg/m2. Transient decreases in RBC polyamine levels were observed in only 3 of 22 subjects; all of the others showed an increase in the levels at some time during DFMO administration. In contrast to these findings, 17 of 22 subjects showed a decline in urinary polyamines; 10 of 22 showed this decline by the end of the first month and the remaining subjects during subsequent administration of the drug. One subject with familial polyposis who had high RBC and urinary polyamine levels prior to DFMO treatment showed a significant decline in urinary polyamines and responded to DFMO treatment with nearly complete resolution of the polyps in the rectal stump. Our results suggest that (a) DFMO concentrations achieved in this study are adequate to modulate polyamine pools as reflected by their reduced urinary excretion; (b) the red blood cell polyamines are not reliable indicators of DFMO activity; and (c) the modulation of polyamines occurs at doses of DFMO that are tolerated by a majority of the subjects.

Administration, Oral↗
PubMedDate not supplied

Sequence specific antisense oligonucleotide analog interference with spermidine/spermine N1-acetyltransferase gene expression.

Induction of the polyamine acetylating enzyme, spermidine/spermine N1-acetyltransferase (SSAT), is one of several biochemical effects associated with the antiproliferative action of polyamine analogs such as N1, N11 diethylnorspermine (DENSPM). Findings to date indicate that this complex and extremely potent gene response involves increased gene transcription, stabilization of mRNA, enhanced translation and protein stabilization. In this study, SSAT-directed antisense oligonucleotide analogs (AOs) were studied for their ability to prevent enzyme induction by DENSPM. Nine 18-mer fully phosphorothioate modified AOs targeting the start codon, exon 6, stop codon and polyadenylation regions of the human SSAT mRNA were synthesized and evaluated in MALME-3M human melanoma cells prior to and during a 6 hr treatment with 10 microM DENSPM. The most effective AOs were those targeting sequences in the stop codon region. Of these, AO-82 suppressed DENSPM induction of SSAT activity, enzyme protein and mRNA by 70-80%. The quantitative similarity of these effects suggests AO interference with mRNA stabilization, a property apparently mediated by sequences located in the stop codon region. Growth inhibition by DENSPM in the presence of the terminally phophorothioated analogs of AO-82 remained similar to that produced by DENSPM alone. While it is possible that SSAT induction may not be involved in analog-mediated antiproliferative activity, a more likely interpretation is that the approximately 50% suppression of the enzyme response achieved in growth studies is not sufficient to abrogate growth inhibition.

Acetyltransferases↗