Proton relaxation times and interstitial fluid pressure in human melanoma xenografts

Abstract

Summary The interstitial fluid pressure (IFP) and the proton spin-lattice and spin-spin relaxation times (T, and T2) of some experimental tumours have been shown to be related to tumour water content. These observations have led to the hypothesis that magnetic resonance imaging (MRI) might be a clinically useful non-invasive method for assessment of tumour IFP. The purpose of the work reported here was to examine the general validity of this hypothesis. R-1 8 human melanoma xenografts grown intradermally in Balb/c nu/nu mice were used as the tumour model system. Median T, and T2 were determined by spin-echo MRI using a 1 .5-T clinical whole-body tomograph. IFP was measured using the wick-in-needle technique. No correlation was found between tumour IFP and fractional tumour water content. Moreover, there was no correlation between median T, or T2 and IFP, suggesting that proton T, and T2 values determined by MRI cannot be used clinically to assess tumour IFP and thereby to predict the uptake of macromolecular therapeutic agents.Keywords: melanoma xenografts; interstitial fluid pressure; magnetic resonance imaging; relaxation times; tumour water content Most tumours show an elevated interstitial fluid pressure (IFP) compared with normal tissues (Jain, 1987). Highly elevated IFP might lead to a pressure difference between the microvascular and interstitial space that is close to 0 mmHg and hence to inadequate uptake and heterogeneous distribution of monoclonal antibodies and other macromolecular therapeutic agents (Jain and Baxter, 1988;Cobb, 1989). Many human tumours show a maximum antibody uptake per gram of tissue of only around 0.005% of the injected dose per gram of body weight (Bradwell et al, 1985). Antibodies are preferentially distributed in regions close to blood vessels, and there are many regions without or with negligible antibody uptake (Jones et al 1986;Sands et al, 1988).Measurements of IFP in human tumours using the wickin-needle technique have shown that the IFP can differ substantially among individual tumours of the same histological type (Boucher et al, 1991;Less et al, 1992). Patients with tumours showing an IFP close to normal tissue values, i.e. tumours with a significant pressure difference between the microvascular and interstitial space are more likely to benefit from treatment modalities involving macromolecular therapeutic agents than patients with highly elevated tumour IFP (Jain and Baxter, 1988). The wickin-needle technique is invasive and can be used to measure IFP only in superficial tumours. A non-invasive method for measurement of IFP would therefore be useful for predicting the uptake of macromolecules in tumours and hence therapeutic response.Studies of experimental tumours have suggested that the IFP is related to tumour water content in some tumour lines (Lee et al, 1992;Leunig et al, 1994). The proton spin-lattice and spin-spin relaxation times (T1 and T2) of tumour tissue are, to a large extent, (Braunschweiger et al, 1986;Belfi et al, 1991). These observations have le...

Quantified Tumor T1 Is a Generic Early-Response Imaging Biomarker for Chemotherapy Reflecting Cell Viability

“…Although in principle the MTR and T 1 are both susceptible to macromolecular content, T 1 is more sensitive at detecting the free mobility of water, whereas MTR measures the exchange rate of bound with free water molecules (46). Consequently, in the RIF-1 tumor, the data obtained in situ supports the hypothesis that a decrease in T 1 reflected an increase in the extracellular space and/or overall permeability, in contrast to untreated tumors where an increase in extracellular space caused an increase in T 1 (16,(18)(19)(20)(21). We suggest that increased permeability leads to a greater amount of serum in the extracellular space, and the increased tissue destruction to higher levels of macromolecules and paramagnetic ions, all of which would lower T 1 .…”

“…Consequently, addition of soluble proteins dose-dependently decreased T 1 (15). Studies of untreated human melanoma xenografts showed that tumor T 1 was correlated positively with extracellular tumor water content (16,(18)(19)(20) and proliferation (21), but negatively with necrosis (18,19). Theoretically, cell destruction would lead to the release of macromolecules and denatured proteins, as well as paramagnetic ions from damaged erythrocytes and thus reduce T 1 .…”

“…Earlier studies using a different method showed that the T 1 of experimental tumors was greater than in normal tissue and was considered to reflect predominantly the extracellular space (14)(15)(16)(17), with a larger interstitial compartment giving a longer (higher) T 1 . In untreated tumors, a low tumor T 1 has been correlated to increased necrosis (16,18), low water content (14)(15)(16)(17)(18)(19)(20), high levels of soluble protein (15), and low proliferation (21). Animals treated with chemotherapy or radiotherapy showed increases (22)(23)(24) and decreases (15,25) in tumor T 1 .…”

Noninvasive Magnetic Resonance Imaging of Transport and Interstitial Fluid Pressure in Ectopic Human Lung Tumors

“…It would therefore be highly useful to develop a noninvasive imaging method that would map the spatial distribution of IFP and the net transfer into the tumor interstitium. An early attempt to use magnetic resonance imaging (MRI) for mapping IFP was based on correlating proton relaxation rates with IFP values obtained by the wick-in-needle technique (17). However, the results showed that both T 1 and T 2 relaxation rates did not correlate with the measured IFP (17).…”

“…An early attempt to use magnetic resonance imaging (MRI) for mapping IFP was based on correlating proton relaxation rates with IFP values obtained by the wick-in-needle technique (17). However, the results showed that both T 1 and T 2 relaxation rates did not correlate with the measured IFP (17). Subsequent dynamic contrast-enhanced MRI studies, using a bolus injection of gadolinium-diethylenetriaminepentaacetic acid (GdDTPA), indicated the presence of disparities between the influx and outflux transcapillary transfer constants in breast tumors (18).…”