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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The correlation between mean arterial blood pressure (MABP) and vascular perfusion in SCC-VII/St tumors in mice was compared following administration of three vasoactive drugs: flavone acetic acid (200 mg/kg), hydralazine (5 mg/kg), or nicotinamide (500, 750, and 1000 mg/kg). MABP was measured by the direct method in unanesthetized, unrestrained mice bearing a carotid catheter. Vascular perfusion of the tumor was measured using the 86RbCl extraction method. Body temperature was maintained at 36 degrees to 37 degrees C after drug administration when necessary. All three drugs reduced MABP from a control value of 125 +/- 2 (s.e.) mm Hg in mice without tumors. Flavone acetic acid at this dose had the least effect on blood pressure, with a minimum of 86% of control values at 10 to 20 min, and a return to control values by 1 hr. However, it produced a profound reduction in tumor perfusion that lasted more than 48 hr. Hydralazine and nicotinamide reduced blood pressure to minima between 55% and 69% of control values within 30 min, followed by a gradual return toward control values by about 8 hr. The reduction in tumor perfusion by hydralazine paralleled its effect on blood pressure. However, nicotinamide produced a transitory, although not statistically significant, increase in tumor perfusion at the highest dose given. These data demonstrate that tumor blood flow modification by drugs is not necessarily the result of changes in MABP, and blood pressure changes alone do not inevitably lead to changes in tumor perfusion.
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PMID:Pharmacological modification of tumor blood flow: lack of correlation between alteration of mean arterial blood pressure and changes in tumor perfusion. 153 Jul 55

Pentoxifylline (PENTO), a derivative of methylxanthine, has been reported to improve fluidity of red blood cells (RBC), and thus improve the flux of RBC through narrow capillaries. Additionally, PENTO increases 2,3-DPG levels in RBC, thereby increasing the O2 release from RBC. Nicotinamide (NA) has been known to increase tumor blood flow, reducing the hypoxic cell fractions in the tumors. The purpose of this study was to examine the effects of PENTO alone or in combination with NA (PENTO + NA) on the oxygenation and radio-response of FSaII murine fibrosarcomas of mice. We observed a significantly enhanced, radiation-induced growth delay of the FSaII tumors by the treatment of either single or multiple injections of PENTO. The combination of PENTO and NA further delayed the growth of tumors. The TCD50 of control tumors was about 56.6 Gy, whereas that of PENTO + NA treated tumors was about 31.9 Gy. Thus, TCD50 was modified by a factor of 1.8. PENTO + NA exerted no effect on the acute skin damage of C3H mice after local irradiation and the gastrointestinal death after whole body irradiation. However, PENTO + NA slightly increased the bone marrow death as demonstrated by the decrease in LD50(30) from 5.5 Gy to 5.2 Gy. The average pO2 in the saline-treated control group of FSaII tumors was 8 mmHg and it significantly increased to 19 mmHg in the PENTO + NA treated group (p less than 0.001). We concluded that the PENTO + NA treatment increased the radio-response of tumors by improving tumor oxygenation.
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PMID:Increases in tumor response by pentoxifylline alone or in combination with nicotinamide. 153 Dec 11

We have continued our investigation into the mechanism by which nicotinamide can enhance radiation damage in tumors, using a C3H mouse mammary carcinoma grown in CDF1 mice. Biochemical analysis of tumor extracts showed that nicotinamide (1000 mg/kg; i.p.) increased the ATP/Pi and ATP/ADP + AMP ratios. This change in metabolic activity was consistent with nicotinamide increasing tumor oxygenation. Moreover, the greatest effect occurred 0.5-2.5 hr after drug injection, a time at which radiosensitization by nicotinamide in this tumor had previously been shown to be maximal. These changes were observed without any apparent modification in tumor blood perfusion, measured using the 86-RbCl uptake procedure, and occurred despite nicotinamide producing a 50% decrease in mean arterial blood pressure, estimated directly by a carotid cannulation technique.
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PMID:Biochemical and physiological changes induced by nicotinamide in a C3H mouse mammary carcinoma and CDF1 mice. 153 Dec 12

The changes in pO2 caused by nicotinamide in the FSaII mouse tumor and three different xenografts of human tumors, HP-56, FaDu, and EO1, grown subcutaneously in the legs of mice were studied. The tumor pO2, as measured with microelectrodes, began to rise soon after the host mice were injected intraperitoneally with 500 mg/kg nicotinamide, and it increased continuously for 100-120 min. The rate and magnitude of the increase in tumor pO2 was dependent on the tumor line and also on the tumor size. In FSaII tumors, the increase in pO2 caused by nicotinamide was relatively small in the well-oxygenated small tumors (173 +/- 5 mm3) compared with that in the larger tumors (515 +/- 25 mm3). The blood perfusion in FSaII tumors as measured with the laser Doppler method was also increased by nicotinamide. The growth delay in FSaII tumors induced by X irradiation was enhanced significantly by nicotinamide. It was concluded that the enhancement of radiation damage in the experimental tumors in mice by nicotinamide, as observed in the present study and reported by others, is due to an increase in intratumor pO2, possibly as a result of an increase in blood perfusion.
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PMID:The oxygenation of murine tumor isografts and human tumor xenografts by nicotinamide. 153 57

Several investigators have shown that nicotinamide (NA) may increase the tumor blood flow and/or alleviate temporal fluctuations in tumor blood flow and, consequently, increase pO2. However, the mechanisms of these changes in tumor blood flow are not understood, especially because NA lowers the mean arterial blood pressure in mice. Our hypothesis is that NA may decrease flow resistance in tumors, which would lower vascular pressure and tumor interstitial fluid pressure (TIFP). To test this hypothesis, we measured the physiological parameters: mean arterial blood pressure, TIFP, tumor water content, and hematocrit in C3H mice bearing FSaII tumors, before and after treatment with 500 mg/kg of NA. In control animals, TIFP increased with tumor growth up to 400 mm3, reached a plateau, and then decreased when the tumor size was above 1000 mm3 (n = 135). Tumor water content correlated significantly with TIFT (for tumors less than 500 mm3) (n = 26). NA caused approximately a 15% decrease in mean arterial blood pressure (P less than 0.05) and a 35% decrease in TIFP (P less than 0.001) at 2 h postinjection, without any change in hematocrit. The change in TIFP was found to be tumor size dependent. Specifically, NA decreased the TIFP by 47% (P less than 0.001) and 39% (P less than 0.001) in medium (200 to 500 mm3) and large (500 to 800 mm3) tumors, respectively. The decrease in TIFP in small (less than 200 mm3) and very large (greater than 800 mm3) tumors was not statistically significant (P greater than 0.1). Our results may explain the size-dependent enhancement in pO2 and radiation response reported by I. Lee and C. W. Song (Radiat. Res., 130: 65-71, 1992) for this tumor line. If our results could be confirmed in human tumors in situ, they would have significant implications in noninvasive measurements of TIFP using NMR and in cancer treatment using radiation, chemotherapy, and immunotherapy.
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PMID:Nicotinamide can lower tumor interstitial fluid pressure: mechanistic and therapeutic implications. 153 73

Four human ovarian and breast tumor lines expressing the HER2/neu oncogene were resistant to the cytotoxic and DNA-degradative activity of TNF. The resistance was not associated with altered TNF receptor function because Scatchard analysis of 125I-rTNF binding to HER2/neu-expressing target cells revealed receptors with normal binding parameters. Furthermore, the TNF receptors on the resistant lines were capable of signal transduction as evidence by the induction of ADP-ribose polymerase activity and MHC expression. TNF resistance was not reversed by coincubation with drugs that interrupted the glutathione redox cycle. In addition, although coincubation of HER2/neu-expressing targets with cycloheximide resulted in significant TNF-induced lysis, when compared to HER2/neu-nonexpressing targets similarly treated with cycloheximide, a significant relative resistance was still present. To investigate the role of ADP-ribosylation in the resistance of these targets, we used nontoxic concentrations of two inhibitors of ADP-ribose polymerase, 3-aminobenzamide, and nicotinamide. Both inhibitors completely reversed the resistance of HER2/neu-expressing targets to TNF-mediated cytotoxicity and DNA injury in a concentration-dependent fashion. These inhibitors of ADP-ribose polymerase did not act by down-regulating expression of HER2/neu oncogenes. In contrast, aminobenzamide and nicotinamide significantly diminished TNF-induced cytotoxicity of L929 targets. These data suggest that the activity of ADP-ribose polymerase may play a pivotal role in determining the fate of the target cell during exposure to TNF.
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PMID:Inhibitors of ADP-ribose polymerase decrease the resistance of HER2/neu-expressing cancer cells to the cytotoxic effects of tumor necrosis factor. 167 41

Exposure of Ehrlich ascites tumor cells to 3-aminobenzamide for 60 min resulted in a dose-dependent increase of cellular NAD and ATP levels at a concentration range of 0.3-5 mM. In the cells exposed to 5-methylnicotinamide there was a decrease of both nucleotide levels. As a possible cause for these changes we found a marked inhibition of microsomal NAD glycohydrolase activity by 3-aminobenzamide and a moderate stimulation of this enzyme by 5-methylnicotinamide. Furthermore, 3-aminobenzamide significantly enhanced the cellular uptake of nicotinamide and NAD synthesis, probably by the stimulation of nuclear ATP-NMN adenylyltransferase activity. We show also that the cells containing elevated NAD and ATP levels by the exposure to 3-aminobenzamide became resistant to the 5-azacytidine cytotoxicity.
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PMID:Influence of ADP-ribosyltransferase inhibitors on the intracellular NAD and ATP levels in Ehrlich ascites tumor cells: implication for the altered NAD + ATP-dependent cellular sensitivity to the cytotoxic agents. 169 42

Flunarizine and nicotinamide have previously been shown to increase blood perfusion to experimental mouse tumors and consequently, to increase their sensitivity to X rays. These agents were examined for their ability to alter metabolism, measured by 31P magnetic resonance spectroscopy, in the SCCVII/Ha carcinoma and the KHT sarcoma. Flunarizine at 5 mg/kg I.P. produced a 45% reduction in the ratio of inorganic phosphate to total phosphate (Pi/total) in the SCCVII/Ha tumor but only a 24% reduction in this ratio in the KHT tumor. These effects were seen 45 min after drug administration, and ratios returned to control levels by 90 min. In the SCCVII/Ha tumor, nicotinamide at 1000 mg/kg I.P. reduced Pi/total by 56% from 30 min to at least 2 hr after injection, and the ratio was reduced by 59% in the KHT tumor at 30 min after injection, returning to control levels by 2 hr. For the SCCVII/Ha tumor, the time course for the effects of flunarizine and nicotinamide on the inorganic phosphate ratio coincided with that previously reported for radiosensitization.
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PMID:The measurement of radiosensitizer-induced changes in mouse tumor metabolism by 31P magnetic resonance spectroscopy. 182 81

There is now considerable interest in the possible use of agents which can change blood flow in solid tumors and thereby alter the response of tumors to different treatments. In the current presentation we briefly review the types of agents which have the potential to modify tumor blood flow, using nicotinamide. hydralazine, and pyrazinamide as examples and illustrate how they can be used to improve the response of murine tumors to radiation, hyperthermia and cyclophosphamide.
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PMID:The use of blood flow modifiers to improve the treatment response of solid tumors. 182 63

Chemical modulation of tumor blood flow has until recently received relatively little attention as a therapeutic tool. Developments in the last few years, both in technology and in drug development, have changed this perspective. Fluorescence activated cell sorting techniques have provided evidence for the existence of acutely hypoxic cells resulting from transient fluctuations in microregional tumor blood flow in experimental tumor systems. We have used such techniques to assess the effects of three systemically administered agents, nicotinamide, flunarazine and Flusol-DA, on the amount of acute hypoxia in the SCCVII tumor. The most effective agent identified in this study is the benzamide analog nicotinamide. We suggest that compounds which modulate such hypoxia could well have a role in radiation therapy, particularly when combined with techniques which increase the oxygen carrying capacity of the blood. The potential of tumor blood flow reduction to improve the effectiveness of bioreductive agents administered alone or in combination with radiation and/or hyperthermia, is well established in experimental systems. Further data are presented, which show that combining hydralazine and the beta-blocker propranolol can provide greater reduction in tumor blood flow than observed with hydralazine alone. Potential limitations of drug induced reduction in tumor blood flow are discussed including the possibility of inducing hypoxia in normal tissues.
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PMID:Drug induced perturbations in tumor blood flow: therapeutic potential and possible limitations. 182 64


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