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Biomedical subjects

M R Horsman

Publications and source records attributed to M R Horsman.

At least 19 recordsLinked to original sources
PubMed2005

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations.

Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.

Angiogenesis Inhibitors↗
PubMed2005

Experience with mouse hepatitis virus sanitation in three transplantable murine tumour lines.

Transmission of viral infection by tumour lines or other biological materials may have confounding effects on research. Many research organizations require screening for viral agents of all cell lines, tumours, sera and other biologicals before implantation or inoculation into animal models. Screening for viral contamination is done by the mouse antibody production (MAP) test, by cell culture, or alternatively by direct detection of the viral agents by polymerase chain reaction (PCR). The description of procedures for sanitation of infected cell lines or tumours is sparse. The present report describes the procedures used for sanitation of three transplantable murine tumour lines, which were transplanted in vivo in a mouse hepatitis virus (MHV)-infected colony of mice at the Department of Experimental Clinical Oncology (DECO). The tumours were frozen and serially transplanted three times in a quarantine colony of syngenic mice. Serological examination of the mice transplanted with tumours as well as their cage mates in the quarantine colony did not detect any antibodies against MHV. After repeated serial transplantation in seronegative animals, tumour material was frozen and thawed tumours were later used for transplantation into the newly established virus-free colony of mice at DECO. PCR-based detection of MHV did not reveal any contamination of the tumour examined by this technique, indicating that this murine tumour apparently did not transmit MHV or that MHV was eliminated from the tissue so fast after the infection that it could not be transmitted by the tumour tissue. It is concluded that MHV infection of mice with transplantable murine tumours does not necessarily cause the tumours to be contaminated.

Animals↗
PubMed2004

Tumour-specific enhancement of thermoradiotherapy at mild temperatures by the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid.

The effect of combining the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) with both radiation and hyperthermia treatments was investigated in a transplanted C3H mouse mammary carcinoma and a normal mouse tissue. Tumours were grown on the right rear foot of female CDF1 mice and treated when sized 200 mm3. The foot skin of non-tumour-bearing CDF1 mice was used to assess normal tissue damage. Radiation and hyperthermia were given locally to the tumour/skin of restrained non-anaesthetized animals. DMXAA (20 mg/kg) was dissolved in saline and injected intraperitoneally 1 h after irradiating and then heating started 3 h later. The endpoints were local tumour control within 90 days or the development of moist desquamation in skin between 11 and 23 days after treatment. The radiation dose (+/- 95% confidence intervals) producing local tumour control in 50% of treated animals was 53 (51-55) Gy for radiation alone. This value was significantly (Chi-squared test; p < 0.05) decreased to 47 (42-52) Gy by DMXAA and to 47 (44-51) Gy by heating (41.5 degrees C/60 min) 4 h after irradiation. Combining both DMXAA and heating further reduced this to 30 (26-35) Gy. When the heating temperature was decreased to 40.5 degrees C, the effect of the triple combination was decreased but was still significant compared with radiation + DMXAA or radiation + hyperthermia. However, this enhancement disappeared at 39.5 degrees C. Radiation damage of normal foot skin was not enhanced by combining DMXAA and hyperthermia at 41.5 degrees C. In conclusion, adding DMXAA to thermoradiotherapy at 40.5-41.5 degrees C significantly improved local tumour control without enhancing normal tissue damage. Thus, including a vascular targeting agent in a mild thermoradiotherapy treatment regimen is a useful approach that may lead to a re-evaluation of the use of hyperthermia in cancer treatment.

Animals↗
PubMed2002

Intense inflammation in bladder carcinoma is associated with angiogenesis and indicates good prognosis.

The aim of this study was to investigate the prognostic influence of microvessel density using the hot spot method in 107 patients diagnosed with transitional cell carcinoma of the bladder. In each case, inflammation was found in the invasive carcinoma, therefore we classified the degree of inflammation as minimal, moderate or intense. Microvessel density was then reevaluated in each tumour in areas corresponding to these three categories. Median microvessel density irrespective of degree of inflammation was 71. Areas of minimal, moderate and intense inflammation were found in 48, 92 and 32 tumours. Microvessel density increased significantly with increasing degree of inflammation. Disease-specific survival was improved if areas of intense inflammation were present in the carcinoma (P=0.004). High microvessel density, irrespective of the degree of inflammation, was associated with a significantly better disease-specific survival (P=0.01). Multivariate analysis using death of disease as endpoint demonstrated an independent prognostic value of N-classification (N0, hazard ratio (HR)=1 vs N1, HR=2.89 (range, 1.52-5.52) vs N2, HR=3.61 (range, 1.84-7.08)), and intense inflammation, HR=0.48 (range, 0.24-0.96). Malignancy grade, T classification and microvessel density were not independent significant markers of poor outcome. In conclusion, inflammation was significantly correlated to microvessel density, and areas of intense inflammation were an independent marker of good prognosis.

Carcinoma, Transitional Cell↗
PubMed2001

Combretastatin A-4 disodium phosphate: a vascular targeting agent that improves that improves the anti-tumor effects of hyperthermia, radiation, and mild thermoradiotherapy.

PURPOSE: To investigate the effect of combining the vascular targeting drug combretastatin A-4 disodium phosphate (CA4DP) with hyperthermia, radiation, or mild thermoradiotherapy in a transplanted C3H mouse mammary carcinoma. METHODS AND MATERIALS: The C3H mammary carcinoma was grown on the rear foot of female CDF1 mice and treated when at 200 mm(3) in size. CA4DP was dissolved in saline and injected i.p. Hyperthermia and/or radiation were locally given to tumors in restrained nonanesthetized mice. Tumor response was assessed using either a tumor growth or a tumor control assay. Mouse foot skin was used to assess normal tissue damage. RESULTS: CA4DP significantly enhanced thermal damage in this tumor model. This effect was independent of drug doses between 25-400 mg/kg, but was strongly dependent on the time interval between drug injection and heating, with the greatest improvement seen when CA4DP preceded the heating by 1 h or less. There was also a suggestion of a temperature dependency with a 1.9-fold increase in heat damage at 42.5 degrees C and a 2.6-fold increase at 41.5 and 40.5 degrees C. Heat-induced normal tissue damage was also enhanced by combining CA4DP with heat, but the degree of enhancement was less than that seen in tumors. CA4DP (25 mg/kg) significantly increased radiation-induced local tumor control and this was further enhanced by combining CA4DP with mild temperature (41.5 degrees C, 60 min) heating. CONCLUSIONS: CA4DP improved the anti-tumor effect of hyperthermia, especially at mild temperatures. More importantly, it also increased the tumor response to mild hyperthermia and radiation, which suggests that CA4DP may ultimately have an important application in clinical thermoradiotherapy.

Animals↗
PubMed2001

Effect of changing tumor oxygenation on glycolytic metabolism in a murine C3H mammary carcinoma assessed by in vivo nuclear magnetic resonance spectroscopy.

The rate of conversion of D-[1-(13)C]glucose into [3-(13)C]lactate (apparent glycolytic rate) has been determined in C3H murine mammary carcinomas in vivo using tumor-selective (13)C nuclear magnetic resonance spectroscopy with (1)H-(13)C cross-polarization. Under conditions of acute hypoxia induced by breathing carbon monoxide at 660 ppm, the apparent glycolytic rate was 0.0239 +/- 0.0019 min(-1). The proportion of (13)C label incorporated into [4-(13)C]glutamate (measured in tumor extracts) was 25-fold lower than that incorporated into [3-(13)C]lactate, reflecting a very limited oxidative metabolism during this hypoxic episode. For animals breathing air or carbogen (95% O(2) + 5% CO(2)), the calculated glycolytic rates were correspondingly lower (0.0160 +/- 0.0021 min(-1) and 0.0050 +/- 0.0011 min(-1), respectively). Although (13)C labeling of glutamate at C4 was still an order of magnitude lower than that for lactate at C3 (11-fold for air and 9-fold for carbogen), these ratios did show a greater degree of oxidative metabolism than that seen in animals breathing carbon monoxide at 660 ppm. The marked difference in apparent glycolytic rate for this tumor model between well-oxygenated and hypoxic conditions demonstrates a substantial Pasteur effect (inhibition of glycolysis by oxygen). Dynamic (13)C nuclear magnetic resonance spectroscopy provides a noninvasive estimate of tumor glycolysis that can be used to evaluate the relationship between oxygenation and energy metabolism, and this has potential consequences for the sensitivity of hypoxic cells to treatment and their ability to promote angiogenesis.

Animals↗
PubMed2001

Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations.

Clinical and experimental studies have suggested that tumour hypoxia is associated with poor treatment outcome and that loss of apoptotic potential may play a role in malignant progression of neoplastic cells. The tumour suppressor gene p53 induces apoptosis under certain conditions and microenvironmental tumour hypoxia may select for mutant tumour cells with diminished apoptotic potential due to lack of p53 function. The aim of this study was to evaluate the prognostic relevance of oxygenation status for treatment outcome and to compare pre-treatment tumour oxygenation measurements were done in 31 of those by PCR using DNA extracted from paraffin-embaedded sections (n = 2) or frozen biopsies (n = 29). The overall median of the tumour median pO(2)was 19 mmHg (range 1-58 mmHg). Only 6 tumours had functional p53 mutations and no association was found between mutant p53 and tumour hypoxia. Five out of 6 STS with lower histopathological grade were well-oxygenated whereas high-grade STS were both hypoxic and well-oxygenated. At a median follow-up of 74 months, 16 patients were still alive among 28 available for survival analysis. When stratifying into hypoxic and well-oxygenated tumours patients with the most hypoxic tumours has a statistically poorer disease-specific and overall survival at 5 years. In conclusion hypoxia was an indicator for both a poorer disease specific and overall survival in human STS but hypoxic tumours were not characterized by mutations in the p53 gene.

Adult↗
PubMed2001

Interaction between combretastatin A-4 disodium phosphate and radiation in murine tumors.

BACKGROUND AND PURPOSE: The ability of combretastatin A-4 disodium phosphate (CA4DP) to induce vascular damage and enhance the radiation response of murine tumors was investigated. MATERIALS AND METHODS: A C3H mouse mammary carcinoma transplanted in the foot of CDF1 mice and the KHT mouse sarcoma growing in the leg muscle of C3H/HeJ mice were used. CA4DP was dissolved in saline and injected intraperitoneally. Tumor blood perfusion was estimated using 86RbCl extraction and Hoechst 33342 fluorescent labelling. Necrotic fraction was determined from histological sections. Tumors were locally irradiated in non-anaesthetised mice and response assessed by local tumor control for the C3H mammary carcinoma and in vivo/in vitro clonogenic cell survival for the KHT sarcoma. RESULTS: CA4DP decreased tumor blood perfusion and increased necrosis in a dose-dependent fashion in the C3H mammary carcinoma, which was maximal at 250 mg/kg. The decrease in perfusion and induction of necrosis by CA4DP was more extensive in the KHT sarcoma. CA4DP enhanced radiation damage in both tumor types. In the KHT sarcoma this enhancement was independent of whether the drug was given before or after irradiating, whereas for C3H mammary carcinoma the enhancement was only significant when administered at the same time or after the radiation, with no enhancement seen if CA4DP was given before. These effects were drug-dose dependent. CA4DP did not enhance radiation damage in normal skin. CONCLUSIONS: CA4DP enhanced radiation damage in the two tumor models without enhancing normal tissue damage. These radiation effects were clearly consistent with the anti-vascular action of CA4DP.

Animals↗
PubMed2001

Improving local tumor control by combining vascular targeting drugs, mild hyperthermia and radiation.

Improvement in local control in a foot-implanted (200 mm3) C3H mouse mammary carcinoma by combining vascular targeting drugs, mild hyperthermia and radiation was investigated. The vascular targeting drug was flavone acetic acid (FAA; 150 mg/kg) intraperitoneally injected either 3 h before local tumor water-bath heating or 1 h after local tumor irradiation. For untreated tumors, the average (+/- 1 S.E.) tumor growth time (TGT; time to reach 5 x treatment volume) was 7.1 days (+/- 0.4). This was increased to 9.2 days (+/- 0.7) by using FAA. Heating also increased TGT, the effect being temperature and time dependent, and this heat response was further increased by FAA. The radiation dose (+/- 95% confidence interval) to control 50% of tumors (TCD50) 90 days after irradiation was 52 Gy (50-55) for radiation alone. This was decreased to 42 Gy (39-45) by FAA, 47 Gy (45-50) by heating (41.5 degrees C; 60 min) 4 h after irradiation, and to 28 Gy (22-35) by combining FAA and heat. Thus, vascular targeting drugs can improve the efficacy of mild hyperthermia and radiation.

Animals↗
PubMed2001

Comparative effects of combretastatin A-4 disodium phosphate and 5,6-dimethylxanthenone-4-acetic acid on blood perfusion in a murine tumour and normal tissues.

PURPOSE: To compare the ability of combretastatin A-4 disodium phosphate (CA4DP) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) to change tissue blood perfusion. MATERIALS AND METHODS: The tissues were a C3H mouse mammary carcinoma and various murine normal tissues, with perfusion measured using the 86RbCl extraction technique. RESULTS: CA4DP (250mg/kg; i.p.) reduced tumour perfusion to 34% of that seen in controls within 1 h of injection. It was maintained at this for at least 6 h, returning to control levels by 24 h. This decrease was dose-dependent. DMXAA (25mg/kg; i.p.) caused a 79% reduction in tumour perfusion 6h after injection; no recovery was observed even after 24 h. DMXAA showed no changes at doses below 10 mg/kg. Both CA4DP and DMXAA increased perfusion in the gut, kidney, bladder and lung, while decreasing splenic perfusion. CA4DP tended to decrease perfusion in muscle, while DMXAA increased liver perfusion. These changes in normal tissue perfusion were generally less than those changes seen in tumours. No significant changes were seen in skin. CONCLUSIONS: CA4DP and DMXAA produced a selective and significant reduction in tumour perfusion, but the pattern of change was different. These results suggest how these vascular targeting drugs should be combined with more conventional therapies.

Animals↗
PubMed2001

Improved tumor response by combining radiation and the vascular-damaging drug 5,6-dimethylxanthenone-4-acetic acid.

The interaction between 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and radiation was investigated in two different mouse tumor models and a normal mouse tissue. C3H mouse mammary carcinomas transplanted in the feet of CDF1 mice and KHT mouse sarcomas growing in the leg muscles of C3H/HeJ mice were used. DMXAA was dissolved in saline and injected intraperitoneally. Tumors were irradiated locally in nonanesthetized mice, and response was assessed using tumor growth for the C3H mammary carcinoma and in vivo/in vitro clonogenic cell survival for the KHT sarcoma. DMXAA alone had an antitumor effect in both tumor types, but only at doses above 15 mg/kg. DMXAA also enhanced radiation damage, and again there was a threshold dose. No enhancement was seen in the C3H mammary carcinoma at 10 mg/kg and below, while in the KHT sarcoma, doses above 15 mg/kg were necessary. This enhancement of radiation damage was also dependent on the sequence of and interval between the treatments with DMXAA and radiation. Combining radiation with DMXAA at the maximum tolerated dose (i.e., the highest dose that could be injected without causing any lethality) of either 20 mg/kg (CDF1 mice) or 17.5 mg/kg (C3H/HeJ mice) gave an additive response when the two agents were administered simultaneously. Even greater antitumor effects were achieved when DMXAA was administered 1-3 h after irradiation. However, when administration of DMXAA preceded irradiation, the effect was similar to that seen for radiation alone, suggesting that appropriate timing is essential to maximize the utility of this agent. When such conditions were met, DMXAA was found to increase the tumor response significantly in the absence of an enhancement of radiation damage in normal skin, thus giving rise to therapeutic gain.

Animals↗
PubMed2000

Non-invasive tumour blood perfusion measurement by 2H magnetic resonance.

Deuterium uptake into foot-implanted C3H murine mammary carcinomas was measured non-invasively by 2H NMR spectroscopy at 46 MHz after i.v. injection. The arterial input function (AIF) was estimated from 2H NMR measurements with a second radiofrequency coil externally located over the heart. Tumour and heart data were acquired over the same time period by means of a switch automatically activated every 1.6-3.2 s. Although the AIF data were, in general, partly contaminated by signals from adjacent tissue, a mathematical fitting procedure involving simultaneous fitting of the AIF and the tumour kinetics gave robust results for tumour blood perfusion (TBP): up to four repeat TBP measurements were made in 14 out of 20 untreated animals and TBP could be measured before and after treatment in 14 out of 15 animals. The ability of this technique to measure changes in blood perfusion was assessed using hydralazine, which decreased TBP from 91 to 29 ml 100 g(-1) min(-1) and this was comparable to a 70% reduction in relative TBP measured by laser Doppler flowmetry.

Animals↗
PubMed2000

Targeting tumor blood vessels: an adjuvant strategy for radiation therapy.

BACKGROUND AND PURPOSE: The neovascularization of tumor cells is a prerequisite if a clinically relevant tumor size is to be reached. A continuously expanding vessel network supplying nutritional requirements and removing waste products is essential for continued tumor development, growth and survival. RESULTS: In many tumors, the growing endothelium is unable to fully support the demands of the neoplastic cell population. As a consequence of the inadequacies of the resulting aberrant vasculature, microenvironmental conditions develop in tumors which are not only detrimental to the response of tumors to conventional anticancer treatments, but may lead to or predispose cells to genetic modifications resulting in more aggressive phenotypes and higher metastatic potential. Yet the utter dependence of the tumor on its induced vessel formation for growth, survival and spread has also created a great deal of enthusiasm for developing therapeutic approaches to specifically targeting the tumor microcirculation. CONCLUSIONS: The application of such strategies as adjuvants to conventional radiation treatments offers unique opportunities to develop more effective cancer therapies.

Blood Vessels↗
PubMed2000

Feasibility of detecting hypoxia in experimental mouse tumours with 18F-fluorinated tracers and positron emission tomography--a study evaluating [18F]Fluoro-2-deoxy-D-glucose.

The study was designed to investigate the binding of [18F]Fluoromisonidazole ([18F]FMISO) and [18F]Fluoro-2-deoxy-D-glucose ([18F]FDG) in a C3H mouse mammary carcinoma. Non-anaesthetized tumour-bearing animals breathing either normal air or carbogen (to reduce tumour hypoxia) were examined by PET after tracer injection. Tumours were identified by radioactive labelling and methods of defining regions of interest (ROI) in the tumours were investigated. Reference tissue was selected elsewhere in the mice and the ratio between mean radioactivity in tumour and reference tissue was compared. The results showed a correlation between the methods of identifying ROIs and a significantly lower tumour to reference tissue ratio for carbogen-treated mice compared with controls when using [18F]FMISO. Only one of the methods showed a significant difference in the tumour labelling between treatment groups using [18F]FDG. The study supports the contention that [18F]FMISO may be able to identify hypoxia in tumours, whereas a similar role for [18F]FDG is more doubtful.

Animals↗
PubMed2000

Combretastatins novel vascular targeting drugs for improving anti-cancer therapy. Combretastatins and conventional therapy.

Combretastatins are a new class of compounds that appear to have anti-tumour activity as a result of specifically targeting the vasculature of tumours. The aim of this study was to investigate the potential of combretastatin A-4 disodium phosphate (CA4DP) to induce vascular effects in a C3H mouse mammary carcinoma, and to see if the anti-tumour response could be improved by combining the drug with conventional anti-cancer therapies. It was found that CA4DP (250 mg/kg) significantly decreased tumour perfusion within 30 minutes after injection and maintained this decrease for several hours, although there was a return to normal by 24 hours. Similar changes were seen in the tumours bioenergetic and oxygenation status. The drug also significantly increased tumour necrosis and had a small inhibitory effect on tumour growth. It was also able to enhance the tumour response to radiation and hyperthermia, when given at the same time or 30 minutes after the radiation and hyperthermia, respectively. Giving the drug 1 hour after cisplatin injection only resulted in a tumour response that was no greater than additive. These results confirm the anti-vascular effects of CA4DP and demonstrate its potential to enhance the anti-tumour activity of conventional therapy.

Animals↗
PubMed1999

Localized in vivo 1H NMR spectroscopy of murine tumours: effect of blood flow reduction.

Single voxel 1H localized spectroscopy (PRESS at 300 MHz) was used to monitor physiological and biochemical changes induced by hydralazine (5 mg/kg, i.p.) in murine C3H mammary tumours. In addition to a significant increase (by 52%, maximal at 30 min) in the intensity of the 1.32 ppm signal (predominantly from lactate, consistent with a selective reduction in tumour blood supply by hydralazine), downfield shifts in the resonance frequencies of 1H signals were observed. In particular, the signal initially at 3.24 ppm (total choline, tCho) shifted by 0.050 ppm (maximal at 13 min), whereas water shifted by 0.086 ppm. Lactate intensity and water and tCho resonance frequencies returned to control values at approximately 100 min after treatment. No significant changes in the resonance frequencies of water or tCho were observed over this time period in the tumours of mice given saline. In vitro studies showed that, while the resonance frequency of water was temperature dependent, the main components of the tCho signal (choline, phosphorylcholine and glycerophosphorylcholine) were more than 30-fold less sensitive to temperature. It was concluded that the shift in the water resonance frequency was due to the combined effects of tumour temperature reduction and a paramagnetic shift from increased deoxyhaemoglobin levels, whereas the tCho signal was only affected by the paramagnetic shifts.

Animals↗
PubMed1999

The ability of hypoxia to modify the gene expression of thymidylate synthase in tumour cells in vivo.

PURPOSE: Hypoxic cells in tumours are resistant to 5-fluorouracil (5-FU). This in vivo study investigated the ability of hypoxia to regulate the gene expression of thymidylate synthase (TS), the target enzyme of 5-FU. MATERIALS AND METHODS: C3H mammary carcinomas, grown in the feet of female CDF1 mice, were used for all experiments. Mice were placed in a 10% oxygen environment for various time periods and the tumour oxygen status was determined with an Eppendorf oxygen electrode. The animals were then injected with BrdU (100 mg/kg, i.p.). Tumours were excised and immediately frozen (-80 degrees C) until isolation of total RNA. The mRNA was reversibly transcribed to complementary DNA and the resulting cDNA amplified in a multiplex PCR reaction, with beta-actin as the internal reference gene. RESULTS: One hour of low oxygen breathing made tumours significantly more hypoxic. This increase was maintained for a maximum incubation period of 48 h. In the same tumours, no change in TS gene expression was seen with up to 3 h of low oxygen breathing. At longer times it decreased, reaching significance at 12-24 h and remaining at this lower level for up to 48 h. BrdU labelling was significantly reduced after breathing low O2 for 24 h (p = 0.001). CONCLUSION: Hypoxia-induced down-regulation of TS gene expression was observed. This would be expected to make hypoxic tumour cells more sensitive to 5-FU. Other mechanisms must be responsible for the previously reported resistance to this drug.

Animals↗