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PubMed1979

In vitro response to rosette inhibition factor (RIF) and rosette restoring factor (RRF) of human lymphocyte after fractionation on a discontinuous density albumin gradient.

In vitro studies on peripheral blood lymphocytes from tuberculous patients and healthy subjects are reported. Factors isolated from human serum used in the experiments included the Rosette Inhibition Factor (RIF) from serum of tuberculous patients and the Rosette Restoring Factor (RRF) from serum of healthy subjects. Lymphocytes were fractionated on a discontinuous BSA gradient. Lymphocytes from healthy subjects, sensitive to RIF, as well as lymphocytes from tuberculous patients, sensitive to RRF, were localized in the third fraction of the BSA gradient. A small percentage of bone marrow cells upon coming into contact with RRF spontaneously formed rosettes with SRBC and were also localized in the third fraction after centrifugation in discontinuous BSA gradient. The results indicate that RIF and RRF act on the same subpopulations, probably precursors of T cells.

Blood Donors↗

PubMed1988

Effect of cyclophosphamide on the pathophysiology of RIF-1 solid tumors.

The present experiments were conducted to determine the effects of cyclophosphamide (150 mg/kg) on the pathophysiology of RIF-1 solid tumors and to determine the temporal relationship between treatment mediated changes in tumor vascular physiology, cell proliferation, and chemoresponsiveness in vivo. Capillary permeability and plasma and extracellular water volumes were determined by a 125I-bovine serum albumin, 51Cr-EDTA double isotope dilution assay at various intervals after cyclophosphamide. Tumor blood flow and exchangeable erythrocyte vascular volumes were determined by 86RbCl distribution and 51Cr-labeled erythrocyte dilution methods. Cell proliferation in RIF-1 tumors, assessed by [3H]thymidine labeling index and tumor growth fraction (primer-dependent DNA polymerase labeling assay) measurements, was inhibited for up to 3 days by cyclophosphamide. Although tumor regrowth was not apparent until Day 10, cell kinetic studies indicated proliferative recovery in the surviving cell population on Days 4 and 5 after treatment. Increases in tumor blood flow and tumor vascular volumes were temporally coincident with this proliferative response. In split-dose experiments, the time-dependent increases in the chemoresponsiveness of RIF-1 tumors, after cyclophosphamide, may be due not only to the increased proliferation of repopulating cells, but also to vascular responses attendant with cytoreduction.

Animals↗

PubMed1986

Effect of dexamethasone on vascular function in RIF-1 tumors.

The present series of experiments was conducted to determine the effect of dexamethasone on vascular function and cell proliferation in s.c. RIF-1 tumors. 125I-BSA, 51Cr-EDTA dilution techniques were used to evaluate dexamethasone induced changes in tumor plasma water, capillary permeability, and extracellular water volumes, while 59Fe and 51Cr labeled erythrocyte techniques were used to assess changes in tumor exchangeable erythrocyte volumes. 86RbCl distribution studies were also conducted to evaluate vascular perfusion in RIF-1 tumors after dexamethasone treatment. In this corticosteroid receptor containing tumor model, dexamethasone had profound effects on all of the measured parameters of vascular function. Reduced tumor cell proliferation after dexamethasone treatments was accompanied by reduced capillary permeability, reduced interstitial water volumes, increased plasma volumes, and reduced vascular perfusion. Serial studies after dexamethasone treatments indicated that increases in vascular perfusion preceded proliferative recovery. Intervals of maximal [3H]thymidine labeling after dexamethasone were characterized by transient increases in capillary permeability, interstitial water volumes, and tumor erythrocyte exchange with the general circulation. At intervals of maximal cell proliferation (36-48 h after dex) 86RbCl distribution in tumors was about 3 times that seen in untreated controls. The results seem to indicate that, as in edematous normal tissues, dexamethasone can have profound effects on vascular function and water compartmentalization in RIF-1 tumors.

Animals↗

PubMed1996

Effects of interstitial heating on the RIF-1 tumor using an Nd:YAG laser with multiple fibers.

BACKGROUND AND OBJECTIVE: Hyperthermia was induced in tumor-bearing C3H mice using a Nd:YAG laser emitting near-infrared radiation at 1,064 nm. The efficacy of multiple implanted fiberoptics in the control of the RIF-1 tumor was investigated. STUDY DESIGN/MATERIALS AND METHODS: RIF-1 tumors in the right hind leg were heated interstitially at 42, 44, or 46 degrees C for 30 or 60 minutes. Two, three, or four 400-microns quartz fibers terminating in a 1.0-cm cylindrical diffusor were inserted into each tumor, as were five microthermocouples to monitor temperature during treatment. Laser Doppler Flow (LDF) was also recorded pre- and post-treatment to determine changes in red blood cell flux in overlying skin (42, 44, or 46 degrees C) and the center of the tumor (46 degrees C). RESULTS: These experiments indicated that interstitial heating at 42, 44, and 46 degrees C resulted in tumor growth delay, although long-term control of tumors was not achieved. Treatment using four fibers resulted in the greatest tumor growth delay at 42 and 44 degrees C, increasing tumor doubling time by 50% or greater compared to control tumors; tumor growth delay following 46 degrees C treatments was seven times greater than that in control tumors. Significant changes (decreases) in LDF (P < .05) were seen in four treatment groups, using two fibers at 42 degrees C for 30 minutes, four fibers at 44 and 46 degrees C for 60 minutes on the overlying skin, and 46 degrees C for 60 minutes in the center of the tumor. CONCLUSIONS: Initial data indicate that interstitial heating with multiple fibers increases tumor growth delay compared to previous single fiber treatments, with tumor growth delay increasing with increasing treatment temperature; however, long-term tumor control was not achieved under the conditions investigated. Follow-up studies will explore the use of higher temperatures and/or longer treatment times in order to optimize tumor response.

Animals↗

PubMed1996

Inhibition of tumor cell proliferation by dexamethasone: 31P NMR studies of RIF-1 fibrosarcoma cells perfused in vitro.

The impact on tumor cell metabolism of a substantial reduction in cell proliferation rate without acute cytotoxicity was examined in cultured RIF-1 tumor cells following treatment with an antiproliferative steroid, dexamethasone (DEX). After 48 h exposure to 4 mM DEX, acute cell viability was essentially unchanged: cells were 93 +/- 2% trypan blue excluding in both control and treated cultures (all values are mean +/- SD). The fraction of actively proliferating cells in the S phase (as indicated by incorporation of 5-bromodeoxyuridine) was only 4 +/- 3%, compared with 13 +/- 3% in age-matched control cultures (n =4, paired t-test: p < 0.004) and 23 +/- 7% at the beginning of the treatment. Three days of DEX treatment resulted in a limited increase in the level of apoptosis (programmed cell death): cells did not become rounded or detached, but the fraction expressing apoptotic DNA fragmentation (susceptible to nick end labeling by terminal deoxy-nucleotidyl transferase) was 15 +/- 7%, vs 2 +/- 1% in control cultures (p < 0.02). Despite a 75% inhibition of cell proliferation, DEX caused only a modest change in the 31P NMR spectra of RIF-1 cells in vitro. The ratio of phosphocreatine to nucleoside triphosphates (NTP) was 30% higher, on average, in treated than in control cells (n = 8, paired t-test, p < 0.02), even when both treated and control cell densities were low. The level of total phosphomonoester (relative to NTP) was lower at low cell density, but this was independent of whether cells were growing rapidly (control low density) or were growth inhibited by DEX. Neither the ratio of phosphocholine to NTP nor the intracellular pH was significantly different in DEX-treated cells.

Animals↗

PubMed1993

Evaluation of changes in oxygen tension as indicators of RIF-1 tumor response to Nd:YAG laser heating.

Heat-induced oxygen tension changes in RIF-1 tumors in C3H male mice were analyzed in an attempt to correlate these changes with tumor response to Nd:YAG laser heating. A low power, microprocessor-controlled Nd:YAG laser was used to superficially heat 250-300 mm3 tumors to base temperatures of 44, 45, 46, or 48 degrees C for 30 minutes via a flexible 600 microns quartz fiberoptic with a terminating microlens. A glass, Clark-style microelectrode was inserted into the center of each tumor allowing real time measurement of the tumor's oxygenation status before, during, and after heating. Results showed that heating at 44 degrees C caused a greater than 2-fold increase in oxygen tension during heating, while a temperature of 48 degrees C caused a brief initial increase in oxygen tension followed by a decrease to below pretreatment values. There was a significant correlation (P < 0.05) between relative tumor oxygen tension during and post-heating and tumor growth delay. A significant correlation (P < 0.05) was also seen between tumor base temperature during heating and tumor growth delay. It appears from our initial data that single point oxygen tension measurements in small RIF-1 tumors may be useful indicators of this model's response to Nd:YAG laser heating. This result may allow for modification of heating parameters (temperature/time) during treatment to optimize thermal response.

Aluminum Silicates↗

PubMed2002

In vivo measurement of regional oxygenation and imaging of redox status in RIF-1 murine tumor: effect of carbogen-breathing.

The purpose of this study was to noninvasively monitor tumor oxygenation and redox status during hyperoxygenation treatment, such as carbogen-breathing, in a murine tumor model using in vivo electron paramagnetic resonance (EPR) spectroscopy and imaging techniques. The study was performed using implanted lithium phthalocyanine (LiPc) microcrystals as the oximetry probe and 3-carbamoylproxyl (3-CP) as the redox probe in RIF-1 tumors implanted in the upper hind leg of C3H mice. Repetitive measurements of pO(2) from the same tumors as a function of tumor growth (8-24 mm in size) showed that the tumors were hypoxic and that the tumor pO(2) values were decreasing with tumor growth. Carbogen-breathing mostly showed an increase in the tumor oxygenation, although there were considerable variations in the magnitude of change among the tumors. The pharmacokinetic studies with 3-CP showed a significant decrease in the overall tumor reduction status in the carbogen-breathing mice. Spatially resolved (imaging) pharmacokinetic data over the tumor volume were obtained to visualize the distribution of the redox status within the tumor. The redox images of the tumor in the air-breathing mice showed significant heterogeneity in the magnitude and spatial distribution of reducing equivalents. On carbogen-breathing the tissue reduction status decreased considerably, with a concomitant decrease in the heterogeneity of distribution of the redox status. The results suggest that 1) carbogen-breathing considerably enhances tissue oxygenation and significantly decreases the redox status in RIF-1 tumor, and 2) changes in the magnitude and distribution of the redox status within the tumor volume during carbogen-breathing are correlated with the increased tissue oxygenation.

Animals↗

PubMed1992

Spatial heterogeneity of the metabolic response of RIF-1 tumors to a vasoactive agent evaluated in vivo by one-dimensional 31P chemical-shift imaging.

Localized 31P NMR spectroscopy was used to evaluate the spatial heterogeneity of the metabolic response of RIF-1 tumors to hydralazine. Volume localized 31P spectra were obtained from subcutaneous RIF-1 tumors using one-dimensional chemical-shift imaging, before and 20 min after treatment with 5 mg/kg hydralazine, administered intravenously. Following treatment all of the tumors showed an overall decrease in the ratio of nucleoside triphosphate (NTP) to inorganic phosphate (Pi) and a decrease in pH. However, spatial localization revealed that the reduction in NTP/Pi was not uniform within some tumors. This was partly due to regional differences in the levels of metabolites existing before treatment. Normal tissue adjacent to the tumor did not show a significant decrease in high-energy metabolites or pH.

Animals↗

PubMed1992

Determination of absolute phosphate metabolite concentrations in RIF-1 tumors in vivo by 31P-1H-2H NMR spectroscopy using water as an internal intensity reference.

The absolute metabolite quantification method of Thulborn and Ackerman [J. Magn. Reson. 55, 357 (1983)] in which the tissue water proton signal is used as an internal intensity standard and its more recent variation in which NMR peak intensities are referenced to that of the natural abundance deuterium signal of water [Li et al., SMRM Abstr. 2, 825 (1988); Song et al., Magn. Reson. Med. 25, 45 (1992) have been implemented to obtain absolute phosphate metabolite concentrations in subcutaneous RIF-1 tumors during untreated growth and following treatment with 5-fluorouracil. The equivalence of these two hydrogen isotopes as intensity standards and the validity of their use in the determination of absolute metabolite concentrations in vivo by NMR has been demonstrated. On matched in vivo and extract tumor samples (n = 5), excellent agreement has been obtained between nucleoside triphosphate concentrations determined by NMR and those derived by HPLC analysis for the control tumors. Following 3 days of untreated growth, absolute concentrations of phosphate metabolites in RIF-1 tumors (n = 10) decreased significantly, except for the Pi concentration which did not vary. For the treated tumors (n = 10) there were no changes in metabolite concentrations except for a decrease in the PCr and, possibly, Pi concentrations. The PCr/Pi ratio in the latter tumors did not change. These observations suggest that changes in absolute metabolite concentrations may be more sensitive indices of response to therapy than changes in metabolite peak amplitude ratios, a parameter commonly used to express in vivo NMR data.

Animals↗

PubMed2003

Detecting early response to cyclophosphamide treatment of RIF-1 tumors using selective multiple quantum spectroscopy (SelMQC) and dynamic contrast enhanced imaging.

The purpose of this study was to develop a reliable, noninvasive method for early detection of tumor response to therapy that would facilitate optimization of treatment regimens to the needs of the individual patient. In the present study, the effects of cyclophosphamide (Cp, a widely used alkylating agent) were monitored in a murine radiation induced fibrosarcoma (RIF-1) using in vivo (1)H NMR spectroscopy and imaging to evaluate the potential of these techniques towards early detection of treatment response. Steady-state lactate levels and Gd-DTPA uptake kinetics were measured using selective multiple quantum coherence (Sel-MQC) transfer spectroscopy and dynamic contrast enhanced imaging, respectively in RIF-1 tumors before, 24 and 72 h after 300 mg/kg of Cp administration. High-resolution (1)H NMR spectra of perchloric acid extracts of the tumor were correlated with lactate and glucose concentrations determined enzymatically. In vivo NMR experiments showed a decrease in steady-state lactate to water ratios (5.4 +/- 1.6 to 0.6 +/- 0.5, p < 0.05) and an increase in Gd-DTPA uptake kinetics following treatment response. The data indicate that decreases in lactate result from decreased glycolytic metabolism and an increase in tumor perfusion/permeability. Perchloric acid extracts confirmed the lower lactate levels seen in vivo in treated tumors and also indicated a higher glycerophosphocholine/phosphocholine (GPC/PC) integrated intensity ratio (1.39 +/- 0.09 vs 0.97 +/- 0.04, p < 0.01), indicative of increased membrane degradation following Cp treatment. Steady-state lactate levels provide metabolic information that correlates with changes in tumor physiology measured by Gd-DTPA uptake kinetics with high spatial and temporal resolution. Both of these parameters may be useful for monitoring early tumor response to therapy.

Animals↗

PubMed2004

Effects of temperature on intracellular sodium, pH and cellular energy status in RIF-1 tumor cells.

Most perfused tumor cell experiments are performed at 37 degrees C, the normal healthy body temperature. However, the temperature of subcutaneously implanted tumors in small animals is generally 29-33 degrees C when the rectal temperature of the animal is maintained at 37 degrees C. We have investigated the acute effects of increasing the temperature of perfused radiation-induced-fibrosarcoma (RIF-1) tumor cells from 33 to 37 degrees C (30 min) on intracellular sodium (Na(i)+) , intracellular pH (pH(i)), and bioenergetic status. Heating the cells by 4 degrees C produced a reversible increase in Na(i)+, slight acidification and no change in nucleotide triphosphate to inorganic phosphate ratio (NTP/P(i)) as measured by shift-reagent-aided (23)Na and (31)P NMR spectroscopy. In the presence of 3 microM 5-(N-ethyl-N-isopropyl) amiloride (EIPA), a potent and specific inhibitor of Na(+)/H(+) antiporter, the increase in Na(i)+ during the heating was completely abolished suggesting that the heat induced increase in Na(i)+ was caused by an increase in Na(+)/H(+) antiporter activity. However, the changes in pH(i) with the heating were identical with or without EIPA, indicating that pH(i) is controlled by other ion exchange mechanisms in addition to Na(+)/H(+) antiporter. NTP/P(i) was significantly higher in presence of EIPA for some time points during the heating suggesting that both NTP production and consumption rates may be altered during the heating. These results indicate that a slight increase in temperature from 33 to 37 degrees C induces significant changes in Na(+) physiology largely because of activation of Na(+)/H(+) antiporter but other ion exchange mechanisms are also involved in maintaining pH(i) in the RIF-1 tumor cells. Thus, care must be taken in choosing the temperature for perfused cell studies.

Animals↗

PubMed1993

Synergistic enhancement by interleukin-1 alpha of cisplatin-mediated antitumor activity in RIF-1 tumor-bearing C3H/HeJ mice.

Administration of interleukin-1 alpha (IL-1 alpha) plus certain cytotoxic drugs causes substantially greater clonogenic tumor-cell kill and tumor-regrowth delay than does treatment with either agent alone. IL-1 alpha itself has little effect on tumor growth despite its ability to induce acute hemorrhagic necrosis, restrict tumor blood flow, and cause microvascular injury in a variety of murine model systems. To investigate further IL-1 alpha's ability to enhance the antitumor activity of cytotoxic drugs, we initiated studies to examine the effect of IL-1 alpha on cisplatin (cDDP)-mediated cytotoxicity using the RIF-1 tumor system. The antitumor activity of IL-1 alpha and cDDP was quantitated through standard clonogenic tumor-cell survival assays, a tumor hemorrhagic necrosis assay and tumor-regrowth delay studies, with the interaction between IL-1 alpha and cDDP being analyzed through median dose-effect. In vitro, IL-1 alpha had no enhancing effect on the cDDP-mediated tumor-cell kill. For examination of the in vivo efficacy of this regimen, RIF-1 tumor-bearing C3H/HeJ mice (14 days postimplantation) were treated concurrently with single i.p. injections of IL-1 alpha and/or cDDP at various doses. The increased clonogenic tumor-cell kill obtained with IL-1 alpha/cDDP was dose-dependent, with significant enhancement by IL-1 alpha being observed (P < 0.001), even at the lowest doses tested (2 mg/kg and 6 micrograms/kg for cDDP and IL-1 alpha, respectively), but it did not correlate with an increase in tumor hemorrhage. Using median dose-effect analysis, this interaction was determined to be strongly synergistic. When treated animals were monitored for long-term antitumor effects, combinations with IL-1 alpha significantly increased the tumor-regrowth delay and decreased the fractional tumor volume (P < 0.001). These results demonstrate that IL-1 alpha synergistically enhances cDDP mediated in vivo antitumor activity and suggest that the combination of IL-1 alpha and cDDP may have potential therapeutic application in the design of effective treatment modalities for cancer.

Animals↗

PubMed2006

Elevation of radiolabelled thymidine uptake in RIF-1 fibrosarcoma and HT29 colon adenocarcinoma cells after treatment with thymidylate synthase inhibitors.

PURPOSE: We recently showed an increase in tumour uptake of 2-[(11)C]thymidine in patients with gastrointestinal malignancies after thymidylate synthase (TS) inhibition. To understand the phenomenon in more detail, we investigated whether TS inhibition by different TS inhibitors leads to a dose- and time-dependent change in the uptake of radiolabelled thymidine, and whether radiotracer uptake is related to changes in cell viability resulting from treatment. METHODS: RIF-1 and HT29 cells were treated with the TS inhibitors 5-fluorouracil (5-FU) and AG337 (nolatrexed dihydrochloride), as well as cisplatin as control. The cell viability and net accumulation of [(3)H]thymidine after a 1-h pulse was determined at different times after drug treatment. RESULTS: In both cell lines, [(3)H]thymidine uptake increased after a 2-h treatment with 5-FU, in a dose- and time-dependent manner. [(3)H]thymidine uptake decreased at 24 and 48 h post treatment. AG337 also produced a similar effect. In contrast to the TS inhibitors, cisplatin decreased [(3)H]thymidine uptake in RIF-1 and HT29 cells at all time points. Cell viability was compromised only after 24 h. CONCLUSION: Using two types of TS inhibitor, we have shown an increase in [(3)H]thymidine uptake, in a dose-dependent manner, a few hours after TS inhibition when the cell viability was not compromised. This effect was not seen with a non-TS inhibitor. These findings suggest that 2-[(11)C]thymidine positron emission tomography can be used to study TS inhibition in vivo at early time points when cell viability is not compromised and may therefore be helpful in the development of new TS inhibitors and in differentiating between patients with tumours sensitive to TS inhibitors and those unlikely to respond.

Adenocarcinoma↗

PubMed1993

Vascular morphometry of KHT and RIF-1 murine sarcomas.

Although tumor oxygenation and vascular structure have been studied extensively, previous work has most often been qualitative in nature. To clarify underlying physiological mechanisms, a more quantitative approach is needed. The current work considers two murine tumor lines of differing radiobiological hypoxic fraction (HF), the RIF-1 and the KHT fibrosarcomas. Following intravascular injection of India ink, histological sections were prepared and quantitated in terms of anatomical blood vessel-tumor cell distance distributions and vessel diameters. Vessel diameters increased with increasing tumor volume for RIF-1 tumors, while not changing significantly for the KHT. The fraction of the tumor within a given distance of the nearest blood vessel, varied as a function of: (i) tumor line, (ii) distance from tumor surface, and (iii) tumor volume. For small-volume tumors, intertumor differences in vessel-tumor cell distances correlated with differences in radiobiological HF, while for large-volume tumors, vessel-tumor cell differences were not significantly different between tumor lines. Combining current findings with previously determined intravascular oxyhemoglobin distributions in the same two tumor lines, it was apparent that not only is a substantial portion of the tumor volume beyond the expected oxygen diffusion limits of blood vessels, but, in addition, a relatively low percentage of these vessels is capable of supplying oxygen.

Animals↗

PubMed1982

Ploidy distribution of tumour cells derived from induced and spontaneously arising metastases of a murine radiation-induced sarcoma, RIF-1.

Flow cytometric analysis of the X-radiation-induced sarcoma RIF-1 has shown that the parent tumour is composed of diploid and tetraploid subpopulations of cells, each capable of independent proliferation. We have now examined artificially induced and spontaneously arising metastases of the RIF-1 tumour and have found in both cases that, unlike the parent tumour from which they are derived, they exhibit a single level of ploidy which is stable throughout successive in vivo and in vitro passaging. This finding suggests that at least in this tumour system metastasis is a clonal event.

Animals↗

PubMed1984

Radioprotection of mouse skin vasculature and the RIF-1 fibrosarcoma by WR-2721.

The degree of radioprotection obtained with WR-2721 is critically dependent upon the oxygen tension of the tissue concerned. It was therefore considered of interest to examine the response of vascular tissue, which would be supposedly well oxygenated, to treatment with WR-2721 plus X rays. The response of this tissue is of interest because of its role in late radiation damage. In addition, for therapeutic gain an agent must protect normal tissue without concomitant tumor protection. However, data on tumor radioprotection have been conflicting and therefore the effect of WR-2721 on an experimental tumor was also tested. Vascular damage was assessed using the fact that tumors grow more slowly in irradiated beds (Tumor Bed Effect). The response of the RIF-1 tumor treated in vivo was measured by in vitro assay of clonogenic survival. WR-2721 (400 mg kg-1) injected 30 minutes before 5 to 30 Gy X rays protected skin stroma by a factor of 1.6. However, WR-2721 given 10 to 60 minutes before 20 Gy X rays to the RIF-1 tumor had either no effect or was protective, according to the method of immobilizing the mice during irradiation. Differences between the ways animals are physically restrained for tumor irradiation could account for the conflicting data concerning tumor radioprotection with WR-2721.

Amifostine↗

PubMed1991

Radiation induction of drug resistance in RIF-1: correlation of tumor and cell culture results.

The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual. We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiation doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors.

Animals↗

PubMed1992

Effect of flunarizine on micro-regional distributions of intravascular HbO2 saturations in RIF-1 and KHT sarcomas.

Flunarizine, a calcium channel-blocker, preferentially active on peripheral blood vessels and red blood cells, has previously been shown to increase not only tumor blood flow, but also both chemosensitivity and radiosensitivity. The mechanisms behind these effects are not clear at present, and different tumor lines have been demonstrated to respond quite differently to the same flunarizine treatment. To clarify the underlying mechanisms at the micro-regional level, the present investigation examined the effects of flunarizine on spatially-resolved distributions of intravascular oxyhemoglobin (HbO2) saturations. Tumors were implanted s.c. in the flanks of C3H mice and grown to a volume of 500-1000 mm3. Flunarizine was injected i.p. at 5 mg/kg; animals were anesthetized, and following a 20 min delay, tumors were quick-frozen. HbO2 saturations were determined cryospectrophotometrically at systematically selected sites across each tumor cross-section. Three primary questions were addressed: (a) Does flunarizine have a direct effect on tumor oxygen delivery as measured by intravascular HbO2 saturations? (b) Are changes in oxygen delivery uniformly distributed throughout the tumor volume? (c) Are HbO2 distributions for tumor lines of dissimilar radiobiological hypoxic fraction affected similarly by flunarizine? For KHT tumors, flunarizine substantially increased the % vessels greater than or equal to 10% saturated throughout the tumor volume, with a somewhat larger increase for the interior vessels than for the peripheral vessels. In contrast, for the RIF-1 tumors, HbO2 saturations following flunarizine remained near control levels. These results indicate that fundamental differences in vascular geometry, hemodynamics, or blood rheology may exist between the KHT and RIF-1 tumor lines, and furthermore, that the response of one tumor line to a given blood-flow modifier may be completely unrelated to that of another.

Animals↗