Simultaneous measurements of intravascular and interstitial oxygen partial pressure (Po2) in any tissue have not previously been reported, despite the importance of oxygen in health and in disease. This is due to the limitations of current techniques, both invasive and noninvasive. We have optically measured microscopic profiles of Po2 with high spatial resolution in subcutaneous tissue and transplanted tumors in mice by combining an oxygen-dependent phosphorescence quenching method and a transparent tissue preparation. The strengths of our approach include the ability to follow Po2 in the same location for several weeks and to relate these measurements to local blood flow and vascular architecture. Our results show that (i) Po2 values in blood vessels in well-vascularized regions of a human colon adenocarcinoma xenograft are comparable to those in surrounding arterioles and venules, (i) carbogen (95% 02/5% CO2) breathing increases microvascular P02 in tumors, and (iii) in unanesthetized and anesthetized mice P02 drops to hypoxic values at <200 Am from isolated vessels but drops by <5 mmHg (1 mmlg = 133 Pa) in highiy vascularized tumor regions. Our method should permit noninvasive evaluations of oxygen-modifying agents and offer further mechanistic information about tumor pathophysiology in tissue preparations where the surface of the tissue can be observed.
Melasma is frequently observed in Indian men. The main causative factors among the male patients appeared to be sun-exposure and family history. Melasma in men is definitely less common than in women, but shares the same clinicohistopathological characteristics as in women.
Summary Fluid transport parameters in intracranial tumours influence the delivery of therapeutic agents and the resolution of peritumoral oedema. The tumour and cortex interstitial fluid pressure (IFP) and the cerebrospinal fluid pressure (CSFP) were measured during the growth of brain and pial surface tumours [R3230AC mammary adenocarcinoma (R3230AC) and F98 glioma (F98)] in rats. Intratumoral and intracranial pressures were also measured in rodents and patients treated with dexamethasone, mannitol and furosemide (DMF), and hypocapnia. The results show that (1) for the R3230AC on the pial surface, IFP increased with tumour volume and CSFP increased exponentially for tumours occupying a brain volume of 5% or greater; (2) in F98 with volumes of approximately 10 mm3, IFP decreased from the tumour to the cortex, whereas for tumour volumes > 16 mm3 IFP equilibrates between F98 and the cortex; (3) DMF treatment reduced the IFP of intraparenchymal tumours significantly and induced a pressure gradient from the tumour to the cortex; and (4) in 11 patients with intracranial tumours, the mean IFP was 2.0 ± 2.5 mmHg. In conclusion, the IFP gradient between intraparenchymal tumours and the cortex decreases with tumour growth, and treatment with DMF can increase the pressure difference between the tumour and surrounding brain. The results also suggest that antioedema therapy in patients with brain tumours is responsible in part for the low tumour IFP.Keywords: interstitial fluid pressure; microvascular pressure; brain tumours in rodents; intracranial tumours in patients; antioedema therapy Studies from our group and other investigators have shown that the interstitial fluid pressure (IFP) of human tumours in situ is significantly elevated compared with normal tissues Roh et al, 1991;Gutmann et al, 1992;Less et al, 1992;Curti et al, 1993;Arbit et al, 1994;Nathanson and Nelson, 1994). In most normal tissues the IFP is around 0 mmHg while for the different carcinoma types measured to date the mean IFPs vary between 14 and 30 mmHg. In general, in human and experimental tumours the IFP increases with tumour size (Jain, 1987a;Boucher et al, 1990Boucher et al, , 1991Boucher et al, , 1995Gutmann et al, 1992;Lee et al, 1992;Nathanson and Nelson, 1994). However, in other studies, the IFP was found to be independent of the tumour volume (Less et al, 1992;Curti et al, 1993;Boucher et al, 1995;Tufto and Rofstad, 1995;Znati et al, 1996). Measurements in experimental tumours have demonstrated that (1) the IFP is uniform throughout the centre of tumours and drops steeply in the tumour periphery or in the normal tissue surrounding the tumour (Boucher et al, 1990;Boucher and Jain, 1992;DiResta et al, 1993) and (2) that the hydrostatic and oncotic pressures in the vascular and interstitial space are at or close to equilibrium Jain, 1989, Boucher andStohrer et al, 1995). The similarity in hydrostatic pressures between the microvascular and interstitial space is thought to be a major mechanism limiting the convective delivery of large therapeut...
Summary Tumour necrosis factor-a (TNF-a) reduced the interstitial fluid pressure (IFP) to 54-64% (P<0.05) and the mean arterial blood pressure (MABP) to 70% (P<0.01) of control values after 5 h in three human melanoma tumour lines transplanted to nude mice.Keywords: tumour necrosis factor-a; interstitial fluid pressure; melanoma xenograft; blood pressure Tumour necrosis factor-a (TNF-a) or cachectin has been proposed as a potential anti-cancer agent for clinical application owing to a remarkable activity of this biological response modifier against several types of murine neoplasms (Asher et al., 1987). Furthermore, TNF-a seems to play an important vasodilatory role in host response to septic insults (Tracey et al., 1987), potentially mediated by the release of nitric oxide (NO) from endothelial cells or macrophages (Baudry and Vicaut, 1993;Kilbourn et al., 1990). The combination of TNF-a, melphalan and interferon-y in regional perfusion of human extremity sarcomas and melanomas has resulted in impressive response rates (Vaglini et al., 1994;Lienard et al., 1992), presumably owing to a combined early effect on tumour vasculature and a possible immune enhancement effect of TNF-a (Fraker and Alexander, 1993). A relationship between production of vascular endothelial growth factor (VEGF) and TNF-a cytotoxicity has been demonstrated in vivo, supporting the hypothesis of a vascular effect of TNF-a on tumour tissue (Amikura et al., 1995). Several studies have suggested that increased delivery of macromolecules (e.g. protein-bound chemotherapeutic agents, antibodies and DNA) can be achieved by lowering the interstitial fluid pressure (IFP) (Boucher and Jain, 1992;Boucher et al., 1991;Kristjansen et al., 1993;Zlotecki et al., 1993Zlotecki et al., , 1995 Mean arterial blood pressure Cannulation of the left carotid artery was performed after a longitudinal skin incision above the trachea. After removal of the submandibular gland, the paratracheal muscles were split and the left carotid artery was isolated. The cranial end of the artery was ligated with a 6-0 silk suture and another suture was tied loosely around the central part of the artery. A metal clamp was positioned caudally to stop the blood flow during the cannulation. A polyethylene catheter (PE-10; Becton-Dickinson, Sparks, MD, USA) filled with heparinised saline was inserted through a hole cut proximally to the cranial ligature, and the other suture was tied tightly around the tubing and artery. The clamp was removed and the end of the tubing was connected to a pressure transducer as described previously (Zlotecki et al., 1993
Summary Tumour pH plays a significant role in cancer treatment. However, because of the limitations of the current measurement techniques, spatially and temporally resolved pH data, obtained non-invasively in solid tumours, are not available. Fluorescence ratio imaging microscopy (FRIM) has been used previously for noninvasive, dynamic evaluation of pH in neoplastic tissue in vivo (Martin GR, Jain RK 1994, Cancer Res., 54, 5670 -5674
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