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D J Chaplin

Publications and source records attributed to D J Chaplin.

At least 145 records · Page 8Linked to original sources
PubMed1985

In vitro and in vivo studies of the TRIUMF pion therapy beam.

Patient treatments at TRIUMF (Tri-University Meson Facility, Vancouver, B. C.) use a moving spot raster scan technique where the pion range is modulated in depth for each position of the moving spot. The spot scans in a stepwise fashion and can produce any desired field shape. This approach provides very good dose uniformity across the treatment field and allows maximum flexibility in shaping the treatment volume. Survival of cultured cells has been used as a biological dosimeter to test the isoeffectiveness of the pion dose distributions, which must be shaped in depth to compensate for the depth-dependent LET distribution. Isoeffectiveness across the treatment field has also been verified using this system, which involves irradiating cells supported in a gelatin matrix. The response of pig skin to pion irradiation at TRIUMF has provided a check on the in vivo RBE for acute effects derived from our earlier studies with mouse foot. In addition, the pig skin reactions have been followed for several months to assess the later dermal response. The RBE of our pion beam relative to 270 kVp X rays is approximately 1.5 for both the acute epidermal and the later dermal responses.

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PubMed1984

Potentiation of cyclophosphamide cytotoxicity in vivo: a study with misonidazole and fifteen other 1-substituted 2-nitroimidazoles.

It has recently been reported that compounds more lipophilic than misonidazole are better potentiators of CCNU tumor cytotoxicity in vivo. There is now a need to extend these studies to include other tumors and cytotoxic drugs. In the present study we have shown that misonidazole (MISO) can potentiate cyclophosphamide cytotoxicity in the Lewis lung carcinoma but not in the B16 melanoma. Further studies in the Lewis lung carcinoma, using 15 1-substituted 2-nitroimidazoles possessing a range of octanol:water partition coefficient (P) (from 0.18- greater than 100) have shown that potentiation increases with increasing lipophilicity. The most efficient compounds at administered dose levels of 1.0 and 2.0 mumol/g were Ro-07-1902, benznidazole (Ro-07-1051) and RSU 1050 which possess octanol:water partition coefficients in the range of 2.5-10. However, on the basis of an equitoxic administered dose (1/2LD50/2d), little difference in potentiation is seen over the range of P studied.

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PubMed1983

Radiosensitization in vivo: a study with an homologous series of 2-nitroimidazoles.

An homologous series of 1-(omega-morpholino)alkyl-2-nitroimidazoles, previously reported to be more efficient hypoxic cell radiosensitizers than misonidazole (MIS) in vitro, were evaluated in vivo using the murine Lewis Lung carcinoma. When given i.p. the compounds were 3-20 times more acutely toxic (LD50/2d) than MIS and this toxicity increased with both the number of methylene groups (n) in the side chain and the lipophilicity of the compounds. The compounds sensitized the tumour to single doses of X-rays. On the basis of equimolar administered dose, the most effective compounds, n = 2, 4 and 5, were as efficient as MIS. However, on the basis of the measured concentration of drug in the tumour at the optimum time of irradiation the compounds with n = 4 and n = 5 were less efficient than expected from previously published data in vitro. This is attributed to the basicity of the morpholino nitrogen in these compounds such that at physiological pH the compounds are primarily in an ionized form and hence poorly able to penetrate hypoxic cells.

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PubMedDate not supplied

The effect of therapy on tumour vascular function.

It has been established that malignant tissue as a consequence of abnormal morphogenesis has a structurally abnormal blood supply. These structural and as a consequence functional differences between normal and neoplastic vasculature provide a basis for selective modulation of tumour vascular function. Agents have been identified which can induce both irreversible and reversible effects on tumour blood flow. Hyperthermia, photodynamic therapy, tumour necrosis factor and flavone acetic acid are known to elicit most of their anti-tumour effect via irreversible changes in tumour vascular function. In addition to the extensive tumour cell kill and thus therapeutic potential provided by such chronic modulation of blood flow, acute transient changes in macroregional and microregional tumour blood flow could also play an important role if used appropriately with conventional therapies. The use of this latter type of modulation is discussed with reference to known examples of such 'vasoactive' compounds. It is also emphasized that blood flow changes induced in tumour tissue can be a 'double-edged sword' with detrimental consequences for therapeutic outcome if inappropriate changes are induced, for example, reductions in flow at the time of conventional radiotherapy or chemotherapy by agents not considered to be 'vasoactive'. To emphasize this point examples of blood flow modulation by pimonidazole and cis-platinum, agents that are used in conjunction with radiotherapy, are described.

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PubMedDate not supplied

The in vivo interaction between flavone acetic acid and hyperthermia.

The in vivo interaction between flavone acetic acid (FAA) and hyperthermia was studied in a C3H mammary carcinoma grown in the feet of female CDF1 mice and in normal foot skin. FAA was intraperitoneally injected prior to local tissue heating in restrained non-anaesthetized animals. Alone, FAA at doses of 100 mg/kg and above, inhibited tumour growth in a dose-dependent fashion. FAA also enhanced the tumour response to heat, the effect being dependent on both the time interval between the two modalities and the FAA dose, the greatest effect occurring when FAA doses of > or = 150 mg/kg preceeded heat by 3-48 h. These effects of FAA correlated with the drug's ability to decrease tumour blood perfusion measured using the RbCl extraction procedure. Injecting 150 mg/kg FAA 3 h before heating (42.7 degrees C) resulted in a 2.2-fold increase in tumour heat damage, but had little effect on the response of normal foot skin in non-tumour-bearing mice. However, this treatment gave a 2.0-fold increase in normal tissue damage when the skin experiments were repeated in tumour-bearing animals. These effects in skin occurred in the absence of any blood perfusion changes, but appeared to be associated with FAA-induced TNF-alpha production.

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PubMedDate not supplied

The effects of nicotinamide plus carbogen or pions for microscopic SCCVII tumors.

We evaluated the sensitizing effect of nicotinamide plus carbogen (N&C) and the relative biological effectiveness (RBE) of pions on microscopic tumors where necrotic tumor centers have not yet been established. Female C3H/He mice and SCCVII tumors were used. The irradiation started two days after tumor implantation. In experiment 1, the tumor beds were irradiated at various doses with 250 KVp photons in 5 fractions over 5 days. Nicotinamide (500 mg/kg/mouse/day in 0.2 ml) was injected intraperitoneally (i.p.) 60 min before irradiation, and carbogen (95% O2 + 5% CO2) was flushed at the rate of 10 l/min for 10 min before irradiation and throughout the entire irradiation procedure. In experiment 2, the tumor beds were irradiated at various doses with pions or 250 KVp photons in 10 fractions over 5 days. In both experiments, the mice were observed for 100 days. The rate of tumor appearance was evaluated and the 50% tumor control dose (TCD50) calculated. The sensitizing ratio (SR) of N&C obtained from the TCD50 assay was 1.46 and the RBE of pions was 1.24. The SR of N&C and the RBE of pions were lower for microscopic tumors than those previously reported for macroscopic tumors. These results were probably due to the absence or reduced presence of radiobiological hypoxic component in the microscopic lesion. However, N&C can be considered to provide an advantage for treatment of even clinical microscopic tumors.

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PubMedDate not supplied

Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate.

Combretastatin A4 phosphate has recently been identified by us as an agent which can selectively damage tumour neovasculature. In the current study we establish that combretastatin induces extensive blood flow shutdown in the tumour compared to normal tissues. Histological assessment of vascular shutdown shows that over 90% of vessels are rendered non-functional 6 hrs post-treatment with 100 mg/kg i.p. Measurement of blood flow using a diffusible tracer 86RbCl indicates an overall reduction in perfusion by only 50-60%. This discrepancy probably reflects increased blood flow in the normal tissue vasculature supplying the tumour rim, which is caused by the ischaemia-induced release of vasoactive mediators. The vascular shutdown induced by administration of 100 mg/kg of combretastatin A4 phosphate results in extensive cell loss in the 24 hrs following treatment, however this is not translated into any significant effect on tumour growth. The continued growth of the tumour is attributed to an actively proliferating population of cells at the periphery of the tumour, which are dependent on normal tissue vasculature for their survival. We have attempted to target this residual population by combining combretastatin A4 phosphate with cytotoxic approaches. Cis platinum and radiation have been used. The results show that combretastatin can significantly enhance tumour response to both cis platinum and radiation. In summary, the studies confirm combretastatin A4 phosphate as a novel agent which targets and damages tumour vasculature and, moreover, indicate its potential therapeutic usefulness as an adjuvant to conventional cytotoxic approaches.

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PubMedDate not supplied

Tumor blood flow modifying effect of electrochemotherapy with bleomycin.

BACKGROUND: Electrochemotherapy combines administration of the chemotherapeutic drug, followed by application of electric pulses in order to increase drug delivery into the cells. The aim of this study was to determine the tumor blood flow modifying effect of electrochemotherapy with bleomycin and correlate it with its antitumor effectiveness and extent of tumor necrosis. MATERIALS AND METHODS: Electrochemotherapy of SA-1 subcutaneous tumors in A/J mice was performed by application of electric pulses to the tumors, following administration of bleomycin, and antitumor effectiveness determined by tumor growth delay and tumor cures as well as extent of tumor necrosis. Tumor blood modifying effect of therapy was evaluated by Patent blue staining technique and 86RbCl extraction technique. RESULTS: A good correlation of the two methods evaluating tumor blood flow, Patent blue staining and the established 86RbCl extraction technique was found (r = 0.944). Electrochemotherapy resulted in complete and permanent shut down of tumor blood flow within 12 hours, which lasted for at least 5 days. The results on tumor blood flow reduction correlated well with the good antitumor effectiveness of electrochemotherapy and with the extent of the necrosis in the tumors. CONCLUSIONS: The results indicate that Patent blue staining technique is a simple and reliable method for estimation of tumor blood flow and that antitumor effectiveness of electrochemotherapy with bleomycin could be partly attributed to its tumor blood modifying and anti-vascular effect.

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PubMedDate not supplied

Effects of combretastatin A4 phosphate on endothelial cell morphology in vitro and relationship to tumour vascular targeting activity in vivo.

BACKGROUND: Combretastatin A4 Phosphate (CA4P) is a tubulin binding agent which causes rapid tumour vascular shutdown. It has anti-proliferative and apoptotic effects on dividing endothelial cells after prolonged exposure, but these effects occur on a much longer time scale than the reduction in tumour blood flow. This study compared the time course of CA4P effects on endothelial cell shape and reduction in red cell velocity. METHODS: Endothelial cell area and form factor (1-4 pi x area x perimeter-2) were measured for proliferating and confluent HUVECs after CA4P treatment. Recovery of shape after CA4P and colchicine was compared. Window chamber studies of tumours were used to measure red cell velocity. Results 70% reduction in red cell velocity and 44% reduction in HUVEC form factor occurred by 10 minutes. Proliferating HUVECs underwent greater cell shape change after CA4P, which occurred at lower doses than for confluent cells. Cell shape recovered 24 hours after 30 minutes exposure to CA4P, but not after colchicine. CONCLUSIONS: The similar time course of cell shape change and red cell velocity reduction suggests endothelial cell shape change may be involved early in the in vivo events leading to vascular shutdown. Differences in the recovery from the shape changes induced by CA4P and colchicine could underlie the different toxicity profiles of these drugs.

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PubMedDate not supplied

Cytotoxicity of bioreductive drug tirapazamine is increased by application of electric pulses in SA-1 tumours in mice.

The application of electrical pulses (electroporation) is a local tumour treatment resulting in the facilitated accumulation of non-permeant chemotherapeutic drugs (electrochemotherapy), as well as in the transient reduction of tumour blood flow. The aim of our study was to determine whether the application of electric pulses to the tumour increased the antitumour effectiveness of the bioreductive drug tirapazamine (TPZ). The survival of SA-1 fibrosarcoma cells was 150-fold lower after the exposure of cells for 1 h to TPZ under anoxic compared with normoxic conditions. The exposure of cells to electric pulses did not increase the cytotoxicity of TPZ. However, the in vivo treatment of subcutaneous tumours with a combination of TPZ (i.p. 25 mg/kg) injected 20 min before the application of electrical pulses significantly enhanced tumour response. Treatment with TPZ and electric pulses, repeated three times at 24-hour intervals resulted in tumour growth delay of 7.2 days. The results of our study showed that the observed antitumour effectiveness is unlikely to be due to increased cellular accumulation of TPZ by application of electric pulses, as indicated from in vitro experiments. The effect is more likely to be attributed to increased tumour hypoxia as a consequence of reduced tumour blood flow induced by application of electric pulses.

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PubMedDate not supplied

The cytotoxicity of melphalan and its relationship to pH, hypoxia and drug uptake.

In the present in vitro studies we examined the effect of hypoxia and acidic pH, two important consequences of reduced blood flow in vivo, on the cytotoxicity of melphalan treatment in Chinese hamster V79-WNRE and SiHa human tumor cells. Cells were exposed to various concentrations of melphalan for 1 hr at 37 degrees C under oxic or hypoxic conditions; pH 6.6 or 7.4, and cell survival was measured. The cytotoxicity of melphalan was potentiated by both low pH and hypoxia, in both cell lines. The overall potentiation, expressed as an enhancement ratio (ER), from both hypoxia and low pH was 3.5 in V79-WNRE and 2.9 in SiHa cells. The potentiation of cell killing produced by hypoxia alone (ERHyp) ranged from 1.4 to 1.9, and was greater in V79-WNRE than in SiHa cells. The potentiation from low pH (ERpH) was approximately 2 in both cell lines. HPLC analysis showed substantial intracellular accumulation of melphalan in both cell lines. Hypoxia and reduced pH further enhanced uptake of melphalan but this was not sufficient by itself to account for the increased potentiation of cytotoxicity observed under those conditions.

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