The contribution of extracellular components to the measurement of pHMRS of a variety of rat tumours (nitrosomethyl urea induced mammary tumours, GH3 prolactinomas, Hepatoma 9618a, UA hepatomas and Walker sarcomas) has been assessed. Acid extractable P(i) was between 2.6 and 12.5 mumol/G wet wt depending on tumour type, and of this 53 +/- 4.8% (mean +/- SEM) was MRS-visible. The P(i) content of tumour exudate was 2-3 mM, of interstitial fluid (sampled from a micropore chamber incorporated within a tumour) 1.7 mM, and of blood plasma 1.95 mM. The mean extracellular volumes of the tumours, measured by distribution of 3H2O and [14C]inulin, were 49-55% depending on tumour type and were at least twice that found in normal liver. Calculations suggested that for most tumours with an extracellular volume not exceeding 55%, at least 65% of the P(i)(MRS) signal was derived from intracellular P(i), and thus that pH(MRS) is a measure of pHi. For each tumour type, pHMRS was measured both in 'pulse-acquire' mode at 1.9 T which may include signals from surrounding tissue, and in localized mode at 4.7 T where the signal came uniquely from tumour tissue. The steady state pHMRS was either neutral or on the alkaline side of neutrality (pH range 7.04-7.37). Raised lactate content and decreased buffering capacity (compared to normal tissues) accompanied these neutral to alkaline pH values.(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose: To test the prognostic potential of tumor R 2 * with respect to radiotherapeutic outcome. Blood oxygenation level dependent (BOLD) MRI images are sensitive to changes in deoxyhemoglobin concentration through the transverse MRI relaxation rate R 2 * of tissue water, hence the quantitative measurement of tumor R 2 * may be related to tissue oxygenation. Methods and Materials:Tumor growth inhibition in response to radiation was established for both GH3 prolactinomas and RIF-1 fibrosarcomas with animals breathing either air or carbogen during radiation. In a separate cohort, the baseline R 2 * and carbogen (95% O 2 , 5% CO 2 )-induced ⌬R 2 * of rat GH3 prolactinomas and murine RIF-1 fibrosarcomas were quantified using multigradient echo (MGRE) MRI prior to radiotherapy, and correlated with subsequent tumor growth inhibition in response to ionizing radiation, while the animals breathed air.Results: A radiation dose of 15 Gy caused pronounced growth delay in both tumor models and transient regression of the GH3 prolactinomas. When the animals breathed carbogen during radiation, the growth delay/regression was enhanced only in the GH3 prolactinomas. The GH3 prolactinomas, which exhibit a relatively fast baseline R 2 * and large ⌬R 2 * in response to carbogen breathing prior to radiotherapy, showed a substantial reduction in normalized tumor volume to 66 Ϯ 3% with air breathing and 36 Ϯ 5% with carbogen seven days after 15 Gy irradiation. In contrast, the effect of 15 Gy on the RIF-1 fibrosarcomas, which give a relatively slow baseline R 2 * and negligible ⌬R 2 * response to carbogen prior to treatment, showed a much smaller growth inhibition (143 Ϯ 3% with air, 133 Ϯ 12% with carbogen). IT IS NOW WELL-ESTABLISHED that uncontrolled proliferation of tumor cells together with the aberrant and poorly regulated blood supply of tumors results in the onset and development of hypoxia, and that clonogenic cells within such regions of hypoxia in tumors are resistant to radiotherapy and chemotherapy (1), the latter either through inadequate drug delivery, pH changes (2), or induction of hypoxic stress proteins (3). ConclusionSeveral approaches, e.g., use of hypoxic cell radiosensitizers like misonidazole (4), hyperbaric oxygen (5), and carbogen (95% O 2 , 5% CO 2 ) (6) have focussed on modifying tumor oxygenation, principally for enhancing radiosensitivity. Breathing high-oxygen content gases such as carbogen increases the amount of dissolved oxygen in the plasma, providing more oxygen at the capillary level and hence allowing diffusion of oxygen into hypoxic regions in order to radiosensitize them. The incorporation of 5% CO 2 is believed to counteract any oxygen-induced vasoconstriction (6). A number of studies have shown that carbogen breathing enhances rodent tumor radiosensitivity (7,8) and, in combination with nicotinamide, is currently being re-evaluated in the clinic as a radiosensitizer in the Accelerated Radiotherapy with Carbogen and Nicotinamide (ARCON) trials (9 -11).Methods of rapidly assessing hypoxia in a...

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