Magnetic Resonance Imaging of Human Melanoma Xenograftsin Vivo: Proton Spin—lattice and Spin—spin Relaxation Times Versus Fractional Tumour Water Content and Fraction of Necrotic Tumour Tissue

Abstract

Proton nuclear magnetic resonance (1H-nmr) imaging is used routinely in clinical oncology to provide macroscopic anatomical information, whereas its potential to provide physiological information about tumours is not well explored. To evaluate the potential usefulness of 1H-nmr imaging in the prediction of tumour treatment resistance caused by unfavourable microenvironmental conditions, possible correlations between proton spin-lattice and spin-spin relaxation times (T1 and T2) and physiological parameters of the tumour microenvironment were investigated. Tumours from six human melanoma xenograft lines were included in the study. 1H-nmr imaging was performed at 1.5 T using spin-echo pulse sequences. T1- and T2-distributions were generated from the images. Fractional tumour water content and the fraction of necrotic tumour tissue were measured immediately after 1H-nmr imaging. Significant correlations across tumour lines were found for T1 and T2 versus fractional tumour water content (p < 0.001) as well as for T1 and T2 versus fraction of necrotic tumour tissue (p < 0.05). Tumours with high fractional water contents had high values of T1 and T2, probably caused by free water in the tumour interstitium. Fractional water content is correlated to interstitial fluid pressure in tumours, high interstitial fluid pressure being indicative of high vascular resistance. Tumours with high fractional water contents are thus expected to show regions with radiobiologically hypoxic cells as well as poor intravascular and interstitial transport of many therapeutic agents. T1 and T2 decreased with increasing fraction of necrotic tumour tissue, perhaps because complexed paramagnetic ions were released during development of necrosis. Viable tumour cells adjacent to necrotic regions are usually chronically hypoxic. Tumours with high fractions of necrotic tissue are thus expected to contain significant proportions of radiobiologically hypoxic cells. Consequently, quantitative 1H-nmr imaging has the potential to be developed as an efficient clinical tool in prediction of tumour treatment resistance caused by hypoxia and/or transport barriers for therapeutic agents. However, much work remains to be done before this potential can be adequately evaluated. One problem is that high fractional tumour water contents result in longer T1 and T2 whereas high fractions of necrotic tumour tissue result in shorter T1 and T2; i.e. the two parameters which are indicative of treatment resistance contribute in opposite directions. Another problem is that the correlations for T1 and T2 versus fraction of necrotic tumour tissue are not particularly strong.

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

“…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 .…”

Detection of necrosis in human tumour xenografts by proton magnetic resonance imaging

“…The proton spin-lattice and spin-spin relaxation times (T1 and T2, respectively) in tumours are influenced significantly by the fraction of free to bound water and the presence of paramagnetic ions (Braunschweiger et al, 1986;Negendank et al, 1991). The possibility has therefore been suggested that viable and necrotic regions in tumours might differ in T, and T2 (Banard et al, 1986;Belfi et al, 1991) and hence that MRI might be developed to be an efficient method for detection of necrotic regions in tumours (Dodd et al, 1989;DeJordy et al, 1992;Rofstad et al, 1994). Several in vitro studies of tumour cells and tissues have given results supporting this suggestion (Bakker and Vriend, 1983;Englund et al, 1986;Sillked et al, 1990).…”

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(Hawkins and Phelps, 1988;Steen, 1992).Proton nuclear magnetic resonance imang (MRI) is well established as a diagnostic method in clnical oncology, but has been devoted less attention as a potential method for providing information on metabolic and physiological conditions in tumours (Steen, 1992;Rofstad et al, 1994). The proton spin-lattice and spin-spin relaxation times (T1 and T2, respectively) in tumours are influenced significantly by the fraction of free to bound water and the presence of paramagnetic ions (Braunschweiger et al, 1986;Negendank et al, 1991).

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“…Dark and bright areas in the synthetic spin-echo images (Figures 4a and 5a) al., 1991;DeJordy et al, 1992). T1 and T, have been shown to increase with increasing water content in tumours (Braunschweiger et al, 1986;Belfi et al, 1991;Rofstad et al, 1994). Second, necrotic regions in tumours can contain extravasated erythrocytes, releasing paramagnetic femrc iron during haemoglobin denaturation (Woodruff et al, 1987).…”