ABSTRACT
We have recently demonstrated that cell lines deficient in poly(ADP-ribose) synthesis due to deficiency in the enzyme poly(ADP-ribose) polymerase (PADPRP) or depletion of its substrate NAD+ overexpress GRP78. Furthermore, this overexpression of GRP78 is associated with the acquisition of resistance to topoisomerase II-directed drugs such as etoposide (VP-16); (S. Chatterjee et al., Cancer Res., 54: 4405-4411, 1994). Thus, our studies suggest that interference with NAD+-PADPRP metabolism could provide an important approach to (a) define pathways of GRP78 induction, (b) study the effect of GRP78 on other cellular processes, (c) elucidate the mechanism of GRP78-dependent resistance to topoisomerase II targeted drugs, and (d) modulate responses to chemotherapy in normal and tumor tissues. However, in the in vivo situation, it is impractical to interfere with NAD+-PADPRP metabolism by mutational inactivation of PADPRP or by depletion of its substrate NAD+. Therefore, we have examined several inhibitors of NAD+-PADPRP metabolism including 3-aminobenzamide, PD128763, and 6-aminonicotinamide for their ability to reproduce the results obtained with cell lines deficient in NAD+-PADPRP metabolism relative to the induction of GRP78 and subsequent development of resistance to VP-16. Our studies show that 6-aminoicotinamide treatment is highly effective in the induction of GRP78 and subsequent development of resistance to VP-16, whereas treatment with 3-aminobenzamide or PD128763 does not induce GRP78 and thus does not result in VP-16 resistance.
Subject(s)
Carrier Proteins/biosynthesis , Etoposide/pharmacology , Heat-Shock Proteins , Molecular Chaperones/biosynthesis , Poly(ADP-ribose) Polymerase Inhibitors , 6-Aminonicotinamide/adverse effects , Animals , Benzamides/pharmacology , Carrier Proteins/metabolism , Cricetinae , Cricetulus , Drug Resistance , Endoplasmic Reticulum Chaperone BiP , Etoposide/toxicity , Isoquinolines/pharmacology , Molecular Chaperones/metabolism , NAD/metabolism , Poly(ADP-ribose) Polymerases/metabolism , Substance Withdrawal Syndrome/physiopathology , Transcription, Genetic/drug effectsABSTRACT
Dynamic radionuclide angiography (5-sec. images) with technetium-99m-sulfur colloid proved to be helpful in 5 patients who presented with gastrointestinal bleeding. In 2, intermittently bleeding hypervascular lesions were seen on dynamic but not on static images; in 2 others, the dynamic images demonstrated hypervascular lesions better than the static scans; and in 1, the radionuclide angiogram localized colonic bleeding more accurately because of rapid peristalsis of extravasated tracer. The addition of the radionuclide angiogram to routine scintigraphy for gastrointestinal bleeding may be crucial for identification of hypervascular lesions and precise localization of bleeding sites.
Subject(s)
Gastrointestinal Hemorrhage/diagnostic imaging , Sulfur , Technetium , Adult , Aged , Diagnosis, Differential , Female , Humans , Male , Melena/diagnostic imaging , Middle Aged , Radionuclide Imaging , Technetium Tc 99m Sulfur Colloid , Time FactorsABSTRACT
A case of non-rotation of the bowel is presented wherein volvulus of the colon occurred causing acute obstruction. Spontaneous reduction following a barium enema as well as the patient's history leads us to suspect that volvulus had occurred in the past and was responsible for the intermittent nature of the patient's symptoms. This type of volvulus is distinctly different from midgut volvulus and is a rare complication of the anomaly of intestinal rotation and fixation known as non-rotation of the bowel. Efforts should be made to study patients with malrotation anomalies at a time when they are acutely symptomatic so that intermittent volvulus such as shown here is not overlooked.
