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Biomedical subjects

J Denekamp

Publications and source records attributed to J Denekamp.

At least 217 records · Page 12Linked to original sources
PubMedDate not supplied

The choice of experimental models in cancer research: the key to ultimate success or failure?

The technologies available for assessing the size and physiological status of malignant tumours are becoming more and more sophisticated. Some of these detect phenotypic biochemical alterations resulting from the genetic changes associated with malignant transformation. Many, however, monitor the abnormal relationship between the tumour mass and the host, detecting pathophysiological changes which result from the host/tumour interaction. The most important of these involve the microregional heterogeneities of nutrients resulting from diffusion patterns around abnormal, newly-formed vascular networks, or inflammatory or immune responses of the host to the tumour. In order to validate new technologies for introduction to clinical medicine they are usually extensively tested in experimental models for cancer. The relevance of these models (whether in vitro cell cultures or experimental tumours) must be considered carefully at the outset, with the factors that influence the parameter being measured, e.g., oxygen or energy status, being given special attention. The genetic similarity of tumour and host, the site of tumour growth, the size of the tumour, the burden it imposes and the immunocompetence of the host are all important features of the experimental model. Inappropriate models may give totally misleading information which cannot be extrapolated to human cancers.

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PubMedDate not supplied

In vivo testing of a 2-nitroimidazole radiosensitizer (Ro 03-8799) using repeated administration.

The radiosensitizing efficiency of a novel 2-nitroimidazole (Ro 03-8799) has been compared with that of misonidazole. Each compound was assessed by constructing dose response curves for regrowth delay using a range of drug doses. The concentration of each compound was measured in tumor homogenates with high performance liquid chromatography (HPLC). When compared on the basis of administered dose the new compound was no more efficient than misonidazole. Comparison on the basis of measured tumor concentrations showed that Ro 03-8799 was 3--4 times more efficient than misonidazole, but only at very high drug levels. Previous in vitro studies had shown a constant 10-fold difference in potency. In order to eliminate possible artifacts caused by the short half life in mice, repeated injections of Ro 03-8799 were used to maintain a constant tumor concentration for two hours before irradiation. No increase in effectiveness was observed with prolonged exposure. This is a charged compound whose distribution is pH dependent; gross tumor levels should therefore be interpreted with caution.

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PubMedDate not supplied

Experimental radiotherapy with WR-2721 and misonidazole.

The data from a large series of experiments on mouse skin and tumors are summarized. Radioprotection with WR-2721 has been observed in both tumors and normal tissues. The protection factors are generally, but not always, higher for skin than for tumors. The protection observed in skin is greater for mice irradiated breathing air than for those irradiated in oxygen. It is postulated that the different protection factors observed in different normal tissues and tumors may reflect differences in tissue oxygenation levels. The combination of misonidazole and WR-2721 has been studied in terms of the modification of radiosensitivity and also as the modification of lethal toxicity. An interaction has been observed in all aspects. The toxicity of WR-2721 increases in the presence of misonidazole. The WR-2721 radioprotection of both skin and tumors decreases if the sensitizer is added. Likewise the radiosensitization with misonidazole is diminished when WR-2721 is present. These results indicate an interaction at the site of radiation injury and they also demonstrate that WR-2721 can adequately penetrate into hypoxic tumor cells.

Amifostine↗
PubMedDate not supplied

Radioprotection of mouse skin by WR-2721: the critical influence of oxygen tension.

The epidermal clone assay has been used to study the radioprotective effect of WR-2721 on mouse skin under different conditions of oxygenation and under anoxia. The skin has shown a progressive decrease in sensitivity as the inspired gas was changed from 100% oxygen towards 0% oxygen. Compared with mice breathing 100% oxygen, those breathing air are partially protected. The inspired oxygen concentration to given half the full oxygen effect is 10--12%. The radioprotection observed with 400 mg/kg WR-2721 is markedly dependent on the ambient oxygen concentration. The protection factor is 1.1 or less in mice breathing 5%, 1% of 0% oxygen. Protection is maximal (1.95) in air and in 50% oxygen and diminishes to 1.6 at higher oxygen tensions.

Amifostine↗
PubMedDate not supplied

Chemosensitization of mouse tumors by misonidazole.

The chemosensitizing action of misonidazole when used in combination with chemotherapeutic drugs has been assessed in two mouse tumors. Regrowth delay has been used as the assay, and by producing dose-response curves the effect has been classified as additive or interactive. A very small additive effect was seen with bleomycin and adriamycin. A larger additive effect was seen with cyclophosphamide, and a dose dependent interaction was seen with melphalan. The misonidazole dose needed to produce these effects has a threshold of 0.5--0.75 mg/g. Two other nitroimidazoles (Ro 05-9963 and Ro 03-8799) were no more effective than MISO when used with melphalan or cyclophosphamide, even though Ro 05-9963 was much more cytotoxic as a single agent. A distinct enhancement of normal tissue toxicity (LD50/30) was observed for MISO combined with melphalan or cyclophosphamide in two strains of mice. However, the tumor sensitization was bigger than the normal tissue effect, resulting in a therapeutic gain in 3 out of 4 comparisons.

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PubMedDate not supplied

Reduced thermal sensitivity of the vasculature in a slowly growing tumour.

The thermal sensitivity of a slowly growing murine mammary carcinoma has been studied, and correlated with several vascular parameters. This tumour, CaRH, had previously been shown to be particularly resistant to hyperthermia when applied as 1 h immersion in a 42.8 degrees C water bath, with or without added X-rays. In the present study water bath temperatures of 43, 44 and 45 degrees C were used as well as a more complex system of water bath plus radiofrequency currents which produced a uniform intratumour temperature of 43 degrees C. Following treatment the tumour blood volume and relative capillary perfusion were estimated using radioactive tracer techniques. Only the treatments which gave at least 60 per cent reduction in blood perfusion yielded significant growth delays or thermal radiosensitization. These data have been compared with values for six other murine tumours. If, instead of comparing the exposure temperature, we compare the blood flow reduction, it is seen that all of the tumours are similar in their thermosensitivity. A higher temperature may be needed to cause vascular shutdown in more slowly growing tumours, but it is achieved with an intratumour temperature of 43 degrees C for 1 h. This may correlate with endothelial cell proliferation rates, which are similar in CaRH to the values measured in human tumours. The more rapid vascular expansion of the fast-growing tumours may result in a more fragile and thermosensitive capillary network. The hypoxic fraction, which is a measure of vascular inadequacy, also correlates with thermal sensitivity.

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PubMedDate not supplied

Cell proliferation kinetics of tumours in relation to cancer therapy.

Cell proliferation kinetic differences exist between tumours and their normal tissue of origin, or the normal tissue within which they grow. These differences may help or hinder the therapist in his efforts to eradicate the tumour without excessive harm to the patient. Some aspects of the influence of cell kinetic parameters on therapeutic response and of the therapy on cell kinetic balances are outlined, both for radiotherapy and chemotherapy.

Cell Division↗