Robert J. Fiel
Roswell Park Cancer Institute
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Featured researches published by Robert J. Fiel.
Biochemical and Biophysical Research Communications | 1982
Mark J. Carvlin; Nirmalendu Datta-Gupta; Robert J. Fiel
Recently, the porphyrin photosensitizer meso-tetra(4-N-methyl-pyridyl)-porphine was identified as a DNA-reactive agent demonstrating both electrostatic and intercalative binding. A series of porphyrin derivatives were synthesized and studied to see if similar compounds manifested identical behavior. One derivative, meso-tetra(p-N-trimethylanilinium) porphine did not exhibit intercalation behavior but did show avid binding and novel circular dichroic features when bound to B-form DNA. At an ionic strength of 1.02, the binding constant was found to be on the order of 104 and higher at lower ionic strength. The large binding constants and induced optical activity suggest that at large porphyrin/DNA ratios the final porphyrin · DNA complex may take the form of a suprahelical helix.
Biochemical and Biophysical Research Communications | 1982
Robert J. Fiel; Terry A. Beerman; Ester H. Mark; Nirmalendu Datta-Gupta
Abstract The iron porphyrin derivatives, iron (III) meso-tetra(4-N-methylpyridyl)-porphine (Fe(III)T4MPyP), aceto-iron (III) meso-tetra(3-N-methylpyridyl)porporphine (AcO-Fe(III)T3MPyP), and iron (III) meso-tetra(p-sulfonatophenyl)-porphine (Fe(III)TSPP), have been shown to induce strand scissions in DNA. Incubation of these porphyrins with PM2 DNA results in the conversion of circular supercoiled DNA to the nicked circular duplex form. The presence of dithiothreitol increases the extent of the nicking reaction. Fe(III)TSPP, which, unlike Fe(III)T4MPyP and AcO-Fe(III)T3MPyP, does not bind to DNA, is the least effective of the three porphyrins in inducing strand scissions in PM2. Both Fe(III)T4MPyP and AcO-Fe(III)T3MPyP induce strand scissions in cellular DNA of pre-labeled HeLa S 3 cells while Fe(III)TSPP has a very limited effect.
Photochemistry and Photobiology | 1991
David A. Musser; Robert J. Fiel
Abstract— A series of tumor localizing porphyrins was evaluated with respect to their ability to elicit cutaneous photosensitivity and systemic immunosuppression, two of the most common side effects associated with photodynamic therapy. Using the murine ear swelling response as an indicator, it was found that all the non‐metalloporphyrins caused cutaneous photosensitization. Immunosuppressive effects were noted using hematoporphyrin derivative (HPD) and meso‐tetra(4‐sulfonatophenyl)porphine if sensitization occurred immediately after photoirradiation, but none were evident using Photofrin II (PII) or meso‐tetra(4‐carboxyphenyl)porphine (TCPP). Subsequent studies indicated that PII and TCPP manifested a delayed type immunosuppression similar to that found following UVB photoirradiation. Manganese (III) meso‐tetra(4‐sulfonatophenyl)porphine, a prototype magnetic resonance imaging contrast agent, was also evaluated because of its reported demetallation in vivo. It was found to cause neither cutaneous photosensitivity nor immunosuppression.
Magnetic Resonance Imaging | 1990
Robert J. Fiel; Musser D; E.H. Mark; Richard Mazurchuk; J.J. Alletto
Four manganese meso-sulfonatophenyl porphyrins were prepared, characterized and investigated for their potential as tumor-specific MRI contrast-enhancing agents in mice bearing subcutaneous implants of a mammary carcinoma (SMT-F). The trisulfonated tetraphenyl porphyrin, MnTPPS3 presented the most favorable profile: bio-distribution, tumor concentration and tumor relaxivity, when compared at 24 hr postinjection. Imaging experiments revealed that a time-dependent delineation of tumor morphology occurs in response to MnTPPS3 that appears to correlate with necrotic regions of the tumor.
Cancer Letters | 1988
Robert J. Fiel; Ester H. Mark; Terry Button; Syed Gilani; David A. Musser
In accordance with earlier work the manganese (III) derivative of meso-tetra(4-sulfonatophenyl)porphine (TPPS4) is found to accumulate in the tumors of L1210-bearing mice. The tumor/liver ratio of porphyrin extends from 1.5 to 3.6 over a range of dose and time periods. The subcellular distribution of porphyrin in L1210 tumor and liver, and the tissue distribution (cellular, stroma, soluble) in L1210 tumor indicates that the porphyrin tends to be located predominantly in soluble and stromal fractions. These data are interpreted in terms of the physiology and composition of neoplastic tissue to formalize a mechanism for the localization of Mn(III)TPPS4 in L1210 tumor and a general working hypothesis for the localization of porphyrins in neoplastic tissue. The in vivo stability of Mn(III)TPPS4 is also addressed and is found to be demetallated to a degree of approximately 1% in liver and kidney.
Photochemistry and Photobiology | 1994
Thomas M. Nicotera; Benjamin R. Munson; Robert J. Fiel
Abstract Cationic porphyrins, known to have a high affinity for DNA, are useful tools with which to probe a variety of interactions with DNA. In this study we have examined both DNA strand scission and oxidative DNA base damage, measured by 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) formation, using a photoactivated cis‐dicationic por‐phyrin. The data demonstrated a dose‐dependent formation for each type of DNA damage. Inhibition of strand scission and 8‐OHdG formation with the singlet oxygen scavenger 1,3‐diphenylisobenzofuran and with MgCl2 and no apparent effect by D2O suggests that a singlet oxygen mechanism generated in close proximity to the DNA may be responsible for the damage. However, a nearly complete inhibition of 8‐hydroxy‐2′‐deoxyguanosine formation in 75% D2O and the substantial enhancement of 8‐hydroxy‐2′‐deoxyguanosine formation in a helium atmosphere by photoactivated porphyrin rules out singlet oxygen as a primary mechanism for this process. These data indicate that distinct mechanisms lead to 8‐OHdG formation and strand scission activity.
Magnetic Resonance Imaging | 1991
Margaret Acara; Richard J. Mazurchuk; Peter A. Nickerson; Robert J. Fiel
Magnetic resonance imaging revealed conspicuously hyperintense regions in the papillary area of kidneys of three untreated rats. When the kidneys were examined histologically, a hydronephrosis associated with the presence of bacteria was found. This study relates magnetic resonance images of an early stage of hydronephrosis to its histological picture.
Biochemical Pharmacology | 1995
Paul R. Libby; Benjamin R. Munson; Robert J. Fiel; Carl W. Porter
The effects of six cationic porphyrins on several enzymes involved in polyamine biosynthesis and catabolism have been examined. Both spermidine and spermine synthase were unaffected by the porphyrins at up to 2 mM. By contrast, ornithine and S-adenosylmethionine decarboxylase were inhibited by the nickel and cobalt derivatives of meso-tetrakis(N-methyl-4-pyridiniumyl)porphyrin (T4MPyP) with IC50 values in the 10-100 microM region. Spermidine/spermine N1-acetyltransferase (SSAT) and polyamine oxidase (PAO) were highly sensitive to the six meso-substituted cationic porphyrins tested, with Ki values as low as 6 nM for SSAT and 85 nM for PAO. These inhibitors may prove useful in defining the structural features of the active site of these enzymes.
Archive | 1993
Stephen B. Kahl; Myoung-Seo Koo; Robert M. Straubinger; Leryang R. Huang; Robert J. Fiel; Richard Mazurchuk; James J. Alletto
Porphyrins are a unique class of metal chelating agents that have shown selective affinity for a variety of neoplasms. The highly water-soluble boronated porphyrin known as BOPP has previously been reported to show highly selective uptake and retention in a murine glioma model, and to produce tumor-boron levels well in excess of that needed for therapy.(1) We wish to report the synthesis and testing of a Mn(III) chelate of BOPP which has the potential to serve simultaneously as a tumor-selective 10B delivery agent and as a proton MRI contrast enhancement agent for glioma. The compound is found to selectively localize in a rat 9L gliosarcoma in a fashion very similar to the free base BOPP and to preferentially enhance the tumor/normal brain contrast of T1-weighted images for at least 92 hours. Based on the behavior of BOPP at the corresponding dose, it can be estimated that the tumor boron content of the MnBOPP-treated animals is in the 30 µg/g range at 24 hours.
Advances in Experimental Medicine and Biology | 1994
Thomas M. Nicotera; Robert J. Fiel
The meso-substituted N-methylpyridyl class of cationic porphyrins are known to have a high affinity for DNA (1). As such, they have been useful tools with which to probe nucleic acid structure and to study a broad range of interactions of cationic ligands with DNA. Activation of this class of porphyrins by visible light produces strand scission in the phosphodiester backbone of DNA at relatively low doses and some metallo-analogs are capable of producing strand scission in the dark. Other substituted porphyrins, hematoporphyrins and methylene blue were found to be less effective under similar conditions. The strand scission activity of cationic porphyrins is not clearly understood, although singlet oxygen has been implicated as a reactive species (1). In this report we have examined the mechanism of photo-induced base damage; specifically, the formation of 8-OHdG. Understanding their role in DNA damage may be useful in screening these compounds as potentially useful agents in photodynamic therapy.