Enhancement of chemotherapy and nitroimidazole-induced chemopotentiation by the vasoactive agent hydralazine

Siemann, Dietmar W.

doi:10.1038/bjc.1990.295

Cited by 16 publications

(5 citation statements)

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“…The potentiation of CCNU by misonidazole has also been explained on the basis of altered pharmacokinetics (Siemann, 1990). However, additional factors may be the existing tumour hypoxic fraction and the fact that tumour vascular shutdown would alter both intratumoural pH and hypoxia.…”

Section: Discussionmentioning

confidence: 99%

The influence of hydralazine on the vasculature, blood perfusion and chemosensitivity of MAC tumours

Quinn

Bibby²,

Cox³

et al. 1992

Br J Cancer

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Summary We have studied the influence of the peripheral vasodilator hydralazine (HDZ) on the vasculature and blood perfusion of two members of a series of subcutaneous murine adenocarcinomata of the colon (MAC tumours), and the influence of HDZ on the efficacy and/or toxicity of TCNU and melphalan. The fluorescent DNA stain Hoechst 33342, showed that HDZ caused a shutdown of tumour vasculature, related in magnitude to both dose and tumour differentiation state; 10 mg kg-' caused an 80% vascular shutdown of well differentiated MAC 26 tumours, but only a 50% shutdown of the poorly differentiated MAC 15A tumours. 2.5 mg kg-' was ineffective. The blood perfusion marker 99mTc-HMPAO showed that the normal perfusion of MAC tumours was consistently markedly less than that of lung, liver or kidneys (4-5% of lung perfusion). HDZ (10 mg kg-') decreased MAC 26 perfusion by 63%, and that of MAC 15A by 20%. Again, 2.5 mg kg-') was ineffective. Use of in vivo to in vitro clonogenic assays showed that HDZ (10 mg kg-') potentiated the efficacy of melphalan ( -Omg kg-' i.p.) by a factor of 2.1, and increased the efficacy of TCNU ( -1O mg kg-' i.v., factor = 1.7) when given 10 or 15 min respectively after dosing. However, the addition of HDZ increased the acute bone marrow toxicity of melphalan, but not that of TCNU. The clinical relevance of these results is discussed.An important factor influencing the delivery and therefore effectiveness of antitumour agents is the relative perfusion of tumour and other tissues with blood. It has been known for more than 40 years (Algire & Legallais, 1951) that perfusion of experimental tumours can be manipulated by the use of vasoactive agents, and a recent paper (Hirst & Wood, 1989) cites more than 25 compounds with the demonstrated ability to alter experimental tumour blood flow, the majority of these causing a decrease.Typical of these is the antihypertensive hydralazine (HDZ), which has been shown to decrease the blood flow through experimental tumours when administered at doses ranging from 0.5-10 mg kg-' either intraperitoneally (i.p.) (Brown 1987;Babbs et al., 1982) or intravenously (i.v.) (Chan et al., 1984;. The results presented for the influence of lower doses of HDZ appear contradictory: Kalmus et al. (1990) showed that 0.25 mg kg-' HDZ slightly increased the blood flow through FSall tumours when administered i.p., whereas Brown (1987), showed that, at this dose, HDZ caused a slight decrease in the blood flow through SCCVII tumours. The influence of HDZ on tumour blood flow is thought to be mainly via two mechanisms: firstly the blood vessels within most experimental tumours cannot be dilated because they are poorly formed, lacking smooth muscle and innervation (Denekamp, 1986;Chaplin, 1987), and maximally dilated already (Chaplin, 1987), and secondly, if the level of the arterial blood pressure drops below that of the intratumoural interstitial pressure (reported to be abnormally high (Wiig et al., 1982)), the tumour vasculature will collapse. Also contributing are secondary effe...

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Section: Discussionmentioning

confidence: 99%

The influence of hydralazine on the vasculature, blood perfusion and chemosensitivity of MAC tumours

Quinn

Bibby²,

Cox³

et al. 1992

Br J Cancer

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“…(Siemann, 1990;Siemann et al, 1989Siemann et al, , 1994. Increasing oxygen transport by inhalation of high oxygen content gas is one way to improve tumor oxygenation ).…”

Section: Discussionmentioning

confidence: 99%

“…In preclinical tumor models the vasoactive agent hydralazine can result in reductions in tumor blood perfusion (Siemann, 1990). Tumor cells recovered from animals treated with this vasodilator exhibited a single peak of high EF5 binding, indicating that the majority of cells in the tumor were hypoxic.…”

Section: Discussionmentioning

confidence: 99%

“…5.7% of the cells were in the high EF5 binding peak. A second agent used was hydralazine, a vasodilator that reduces tumor blood perfusion (Siemann, 1990). As expected from an agent that increases tumor hypoxia, EF5 binding was found to increase.…”

Section: Ef5 Binding Following Treatment With Agents That Alter Tumomentioning

confidence: 99%

“…High oxygen content gas inhalation (carbogen, 5% C02/95% 0 2 ) was used to improve tumor oxygenation . Reductions in tumor blood flow and induction of host anemia were achieved through treatments with the vasoactive agent hydralazine (Siemann, 1990) and the hemolytic agent phenylhydrazine hydrochloride (Siemann et al, 1989), respectively.…”

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Direct relationship between radiobiological hypoxia in tumors and monoclonal antibody detection of EF5 cellular adducts

et al. 1996

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While the potential importance of hypoxia in limiting the sensitivity of tumor cells to ionizing radiation has long been appreciated, methods for accurately quantifying the number of radiation-resistant hypoxic cells within tumors have been lacking. We have used the pentafluorinated derivative [2-(2-nitro-I H-imidazol-I -yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide] of etanidazole (EF5). which binds selectively to hypoxic cells. The adducts formed between EF5 and cellular proteins in the hypoxic cells were detected using the specific monoclonal antibody (MAb), ELK3-5 I conjugated to the flurochrome Cy3, and the number of hypoxic cells was quantified by flow cytometry. To verify the validity of this technique for the detection of hypoxic cells, mice bearing KHT sarcomas were treated with various agents to alter tumor oxygenation and hence vary the fraction of radiobiologically hypoxic tumor cells. The percentage of EF5 binding cells was then compared directly with the clonogenic survival of the tumor cells following radiation treatment under the various pretreatment conditions. The results showed that allowing the mice to breathe carbogen (5% C0,/95% 09 prior to irradiation reduced clonogenic cell survival approx. 6-fold and led to an absence of cells binding high levels of EF5. In contrast, pretreating the tumor-bearing animals with either hydralazine, which decreased tumor blood flow, or phenylhydrazine hydrochloride, which made the mice anemic, increased tumor cell survival following irradiation 2-to 4-fold, indicative of an increase in the fraction of hypoxic tumor cells. EF5 measurements made under identical conditions illustrated a shift in the cells in the tumor to high EF5 binding. Our results demonstrate that flow cytometric measurement by fluorescent MAb binding to EF5 adducts may relate directly to radiobiological hypoxia in KHT tumors measured by conventional methods.

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Pharmacokinetic changes induced by vasomodulators in kidneys, livers, muscles, and implanted tumors in rats as measured by dynamic Gd‐DTPA‐enhanced MRI

Wang

Roth

et al. 1996

Magnetic Resonance in Med

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The effects of three physiologically different vasomodulators, angiotensin II (a vasoconstrictor), hydralazine (a vasodilator), and histamine (a permeability modulator), on the pharmaco-kinetics of entry of small molecules (measured by Gd-DTPA concentration) into normal and abnormal tissue were studied in rats implanted with R3230 AC tumors. Sequential dynamic Gd-DTPA-enhanced MRI studies, one before and one after vasomodulator administration, were performed, and the signal intensities of various tissues analyzed. Angiotensin II (6 micrograms/kg) reduced blood flow in tumors, but increased it in muscles. Hydralazine (5 mg/kg) reduced blood flow in tumors, kidneys, and livers, and slowed Gd-DTPA clearance from tumors, livers, and muscles. Histamine (25 micrograms/kg) increased renal blood flow, hastening Gd-DTPA clearance causing reduced measurable blood flow in tumors and muscles. By simultaneously monitoring the effects in various tissues, the pharmacokinetic effect of each drug in the entire body could be obtained.

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Enhancement of chemotherapy and nitroimidazole-induced chemopotentiation by the vasoactive agent hydralazine

Cited by 16 publications

References 24 publications

The influence of hydralazine on the vasculature, blood perfusion and chemosensitivity of MAC tumours

The influence of hydralazine on the vasculature, blood perfusion and chemosensitivity of MAC tumours

Direct relationship between radiobiological hypoxia in tumors and monoclonal antibody detection of EF5 cellular adducts

Pharmacokinetic changes induced by vasomodulators in kidneys, livers, muscles, and implanted tumors in rats as measured by dynamic Gd‐DTPA‐enhanced MRI

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