Search PubMed⌕ Search

Biomedical subjects

J Denekamp

Publications and source records attributed to J Denekamp.

At least 55 records · Page 3Linked to original sources
PubMed1995

Radiosensitization of mouse skin by oxygen and depletion of glutathione.

PURPOSE: To determine the oxygen enhancement ratio (OER) and shape of the oxygen sensitization curve of mouse foot skin, the extent to which glutathione (GSH) depletion radiosensitized skin, and the dependence of such sensitization on the ambient oxygen tension. METHODS AND MATERIALS: The feet of WHT mice were irradiated with single doses of 240 kVp x-rays while mice were exposed to carbogen or gases with oxygen/nitrogen mixtures containing 8-100% O2. The anoxic response was obtained by occluding the blood supply to the leg of anesthetized mice with a tourniquet, surrounding the foot with nitrogen, and allowing the mice to breathe 10% O2. Further experiments were performed to assess the efficacy of this method to obtain an anoxic response. Radiosensitivity of skin was assessed using the acute skin-reaction assay. Glutathione levels were modified using two schedules of DL-buthionine sulphoximine (BSO) and diethylmaleate (DEM), which were considered to produce extensive and intermediate levels of GSH depletion in the skin of the foot during irradiation. RESULTS: Carbogen caused the greatest radiosensitization of skin, with a reproducible enhancement of 2.2 relative to the anoxic response. The OER of 2.2 is lower than other reports for mouse skin. This may indicate that the extremes of oxygenation were not produced, although there was no direct evidence for this. When skin radiosensitivity was plotted against the logarithm of the oxygen tension in the ambient gas, a sigmoid curve with a K value of 17-21% O2 in the ambient gas was obtained. Depletion of GSH caused minimal radiosensitization when skin was irradiated under anoxic or well-oxygenated conditions. Radiosensitization by GSH depletion was maximal at intermediate oxygen tensions of 10-21% O2 in the ambient gas. Increasing the extent of GSH depletion led to increasing radiosensitization, with sensitization enhancement ratios of 1.2 and 1.1, respectively, for extensive and intermediate levels of GSH depletion. In mice exposed to 100% O2, a significant component of skin radiosensitivity was due to diffusion of oxygen directly through the skin. Pentobarbitone anesthesia radiosensitized skin in mice exposed to 100% O2 by a factor of 1.2, but did not further sensitize skin in mice exposed to carbogen. CONCLUSIONS: Glutathione levels and the local oxygen tension at the time of irradiation were important determinants of mouse foot skin radiosensitivity. The extent to which GSH levels altered the radiosensitivity of skin was critically dependent on the local oxygen tension. These results have significant implications for potential clinical application of GSH depletion.

Animals↗
PubMed1995

Combined radioimmunotherapy and radiotherapy of human colon carcinoma grafted in nude mice.

The effect of combined radioimmunotherapy (RIT) and fractionated external beam radiotherapy (RT) was assessed in two human colon cancer xenografts, Co112 and LS174T in nude mice. These tumors were selected for being resistant to RIT alone, as is usually the case in the clinical situation. Tumor-bearing mice were treated with a combination of five X-ray fractions over 5 days followed by RIT with two doses of 1.5 mCi 131I-labeled anticarcinoembryonic antigen monoclonal antibody F(ab')2. In Co112 and LS174T, RIT alone achieved a regrowth delay similar to that of fractionated RT with total doses of 28 and 26 Gy, respectively. In both tumor types, an additive therapeutic effect, measured as increased regrowth delay or local control, was observed when combining RT of different dose levels with RIT. Normal tissue responses were assessed by monitoring acute peak skin reactions and blood cell count. Bone marrow depression for the combination treatment was similar to that of RIT alone; relative to skin, at equitoxic levels, no mice bearing Co112 tumors were locally controlled with a 32 Gy RT dose alone, while this RT combined with RIT gave a local control of 100%. These studies show a therapeutic benefit when external beam RT is combined with RIT.

Animals↗
PubMed1994

The effect of BW12C on the radiosensitivity and necrosis of murine tissues and tumours.

BW12C is a drug that has the potential to induce normal tissue and tumour hypoxia by binding to haemoglobin, increasing its affinity for oxygen and thereby reducing oxygen availability to tissues. Initial results suggested that BW12C administration caused significant radioprotection of normal tissues and induced tumour necrosis, but variable results have been reported subsequently. This work was carried to extend the range of observations concerning the ability of BW12C to radioprotect normal tissues and tumours and to induce necrosis of tumours of the mouse. BW12C was administered as 70 mg/kg i.v. 15 min before irradiation of jejunum in CBA mice and of foot skin in WHT mice with single doses of 240 kVp X-rays while mice breathed gases of varying oxygen tensions. The radiosensitivities of these tissues were assessed by the crypt survival assay and the acute skin reaction, respectively. The radiosensitivity of CaNT tumours to single fraction irradiation was assessed by the regrowth delay assay following administration of single or multiple doses of BW12C at varying times to air-breathing CBA mice. The radiation response was compared to the radiosensitivity of clamped tumours. The effect of BW12C alone on tumours was assessed by regrowth delay and histological examination for necrosis. BW12C did not change the radiosensitivity of jejunal crypts irradiated while mice breathed air or 10% O2, or of foot skin when mice breathed 12% O2. BW12C protected foot skin by a factory of 1.1 when mice breathed air. Single or multiple doses of BW12C did not influence the radiosensitivity of CaNT tumours, although marked radioprotection could be induced by clamping the tumours during irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Neutron radiobiology revisited.

The present paper reviews the experimental results of normal tissue and tumour studies in animals. The dose per fraction dependence of the RBE in normal tissues has been long recognised, together with the steeper increase of RBE at low doses for late responding tissues compared with acute reactions. The dose dependence for tumours is more complex, because of hypoxia and reoxygenation, as well as differences in repair capability after high LET damage. A comparison of tumour and normal tissue RBE values shows that there is little experimental evidence for a therapeutic advantage at clinically relevant doses. In particular, the RBE for slow growing tumours is even lower than that for the faster growing mouse tumours. The reasons for the loss of expected neutron benefits in clinically relevant experiments are discussed. The disappointing prospects for neutrons are contrasted with the current multifactorial approaches to overcoming resistance to more conventional low LET radiations, including acceleration, hyperfractionation and several types of hypoxic cell radiosensitizers.

Animals↗
PubMed1994

Acute effects of accelerated radiotherapy in combination with carbogen breathing and nicotinamide (ARCON).

Combining accelerated radiotherapy with carbogen and nicotinamide (NAM) has been proposed as a strategy to overcome the sparing effect of tumour clonogen repopulation and hypoxia. Six patients with squamous cell carcinomas of the head and neck were given accelerated radiotherapy, carbogen breathing and high dose nicotinamide in order to evaluate the feasibility of this treatment regimen. The patients received radiotherapy in two daily fractions of 1.8-1.9 Gy, five days/week, total dose 54-57.6 Gy, in an overall treatment time of 19-22 days. The interfraction intervals were 7-8 hours between the two fractions on the same day. Carbogen breathing was started 5 minutes before and went on during each radiation fraction. a variety of NAM doses were administered orally in conjunction with radiation therapy and analyses of plasma concentrations of NAM and its metabolites were performed. The most common side-effect from NAM was nausea and vomiting, which in one case hampered further NAM administration. The side effects were not related to plasma levels of NAM or its main metabolites. Additionally, one patient with preexisting heart disease developed a severe hypotension and renal dysfunction. All acute reactions healed without further complications. The mucosal reactions were generally brisk. Thus, the combination of accelerated radiotherapy with carbogen and NAM seems to be tolerable.

Administration, Inhalation↗
PubMed1993

Early and late injuries in mouse rectum after fractionated X-ray and neutron irradiation.

PURPOSE: to assess mouse rectum tolerance to fractionated X-ray and neutron irradiation. MATERIALS AND METHODS: doses per fraction ranged between 0.25 and 35 Gy for X-rays, 0.05 and 12 Gy for neutrons. Neutron top-up doses were added when the fractionated irradiation was given in fractions less than 2 Gy of X-rays or 0.35 Gy of neutrons in order to bring the damage into the detectable range. The early endpoints were the nadir of weight loss occurring within the first 2-3 weeks following irradiation and lethality by 2 months. The late endpoints were the peak of weight reached at maturity of the mice, the proportion of short feces in the daily fecal output at 10 months and lethality by 12 months. The linear-quadratic (LQ) model was fitted to the data (direct "one-step" analysis) and the estimated parameters were used to calculate relative biological effectiveness (RBE) values. RESULTS: alpha/beta ratio estimates were for X-rays: 19.9 Gy [95% confidence limits: 15.2, 27.0] for weight nadir. 13.4 Gy [9.3, 19.5] for early lethality, 6.4 Gy [3.6, 11.0] for peak weight, and 6.9 Gy [4.2, 10.8] for late lethality, for neutrons 19.9 Gy [9.5, 61.0] for peak weight. The fecal-deformity data were poorly fitted by the LQ model. The RBE was slightly higher for acute endpoints than for the late ones when X-ray fraction sizes were equal to or larger than 10 Gy. However, the change in RBE with decreasing X-ray dose per fraction was much steeper for the late endpoints, so that it became equal to or even higher than for acute reactions at doses per fraction of 5 Gy or less. CONCLUSION: Our results were consistent with those obtained from previously published studies using the same experimental system but larger doses per fraction.

Animals↗
PubMed1993

Vinca alkaloids: anti-vascular effects in a murine tumour.

We have investigated the blood flow modifying effects of the vinca alkaloids, vincristine and vinblastine in the murine carcinoma CaNT. Vinblastine at doses of 7.5 or 10 mg/kg induced profound and chronic reductions in tumour blood flow as measured by 86RbCl extraction. Following the maximum tolerated dose of 10 mg/kg, blood flow was reduced to 10% of pretreatment values after 2 h and remained below 20% of pretreatment values 24 h after drug administration. These findings are consistent with the early induction of necrosis by vinblastine and suggest that vascular-mediated cell death may account for a large part of the 11 day growth delay induced by this drug dose. In contrast to the large reductions in tumour blood flow, in skin, kidney, liver and muscle, blood flow reductions did not, at any time examined, exceed 40%. In all the normal tissues studied, blood flow had fully recovered by 6 h after vinblastine administration. Similar results, albeit less pronounced, have been obtained with vincristine at the maximum tolerated dose of 3 mg/kg. The results clearly show that both vinblastine and vincristine can induce, with some selectivity, a dramatic and prolonged reduction in tumour blood flow and that this may contribute to the anti-tumour effects against the CaNT tumour.

Adenocarcinoma↗
PubMed1993

Flavone acetic acid (FAA) with recombinant interleukin-2 (rIL-2) in advanced malignant melanoma: I. Clinical and vascular studies.

A trial of FAA and rIL-2 has been performed both to study the clinical efficacy of this combination and to determine whether they cause haemorrhagic necrosis by acting upon tumour vasculature. FAA and rIL-2 were given to 23 patients with progressing metastatic melanoma. FAA 4.8 gm m-2 was given as a 1 h infusion without urine alkalinisation on days 1, 8 and 15. rIL-2 (6-18 x 10(6) IU/m2/day) was given as a continuous infusion days 8-12 and 15-19 (nine patients) or days 8-12 only (14 patients). Treatment was repeated after 2 weeks unless there was disease progression. Of the 21 assessable patients there have been one complete (skin and liver) and two partial responses (skin and liver, skin and nodes) lasting 20 + 17 + and 15 months, overall response rate 14%. Unexpectedly severe hypotension after the third FAA, when given 2-4 days after RIL-2, was the major toxicity (8/15 grade 3 or 4). No alteration in coagulation parameters were seen during therapy of the first ten patients. No increase in tumour necrosis was seen in any of the 15 biopsies taken from ten patients after therapy. This suggests that FAA does not have similar vascular effects in human as it does in murine tumours.

Adult↗
PubMed1993

Review article: angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy.

A body of evidence that vascular-mediated damage occurs in murine tumours after many existing forms of anti-tumour therapy is rapidly accumulating (see Gray Conference Proceedings edited by Moore & West, 1991). Rapid conventional screens of cells in vitro or using leukaemias of lymphomas will not detect this mode of action and such screens will therefore miss effective agents. A change in the approach to experimental cancer therapy is needed to ensure that this important new avenue is fully investigated. Solid tumours will need to be studied and the importance of specific tumour cell biochemistry (e.g. on tissue factor procoagulant activity), of endothelial status and the immunocompetence of the host are all likely to be important. It is a subject of considerable debate at present whether transplanted subcutaneous mouse tumours are adequate models and whether they will reflect the response of spontaneous tumours, or even of transplants into other sites. Xenografts are not likely to be appropriate if the immuno-suppressed hosts lack the cells needed for the cytokine component of the pathway. The strategy of design and screening of new agents, for scheduling of existing agents and particularly the sequencing of adjunctive therapies are likely to be completely different for the "direct" tumor cell or "indirect" vascular-mediated approaches. It may eventually be appropriate to combine vascular manipulation with direct cytotoxicity aimed at malignant cells but the two mechanisms must be recognized as distinct entities and considered separately before attempting to coordinate them. It is important therefore to identify the "hallmarks" of vascular mediated injury and the means by which this can be distinguished from direct cell kill. These may be detectable in the tumour response but clues can also be gained from the side effects that are seen in normal tissues both with existing and with novel therapies (Figure 7). The appeal of vascular-mediated ischaemic therapy is that it is systemic and will have the potential of being effective on any tumour with a newly evoked vascular network, i.e. of about 1 mm in diameter, but it will be even more effective on large tumours than on small. Thus it should affect both large primary tumours and disseminated small metastases. The studies with many different anti-cancer agents have illustrated the potential complexity of responses that can appear to cause tumour cell death by collapse or occlusion of the blood supply. They have also focused attention on features of disparate agents, e.g. TNF, FAA, PDT, which may share similar pathways. No single feature of neovasculature can be highlighted as the sole route by which such antivascular therapy should be targeted. Rapid proliferation of the endothelial cells may prove to be a target, but it also influences differentiation characteristics, so that the immature cells will function abnormally. The permeability of these poorly formed vessels may lead to extravasation of proteins leading to increase interstitial pressures and by this means to an imbalance between intravascular and extravascular pressures and hence to collapse of the thin-walled vessels. Changes in systemic blood pressure, cardiac output, viscosity or coagulation and especially a redistribution of regional perfusion would all have differential effects in tumours and normal vessels. Clearly both vascular patho-physiology and the complexity of endothelial cell function and its imbalance in neovasculature will be important in understanding the mechanism of action of antivascular strategies. This very challenging boundary between oncology and a number of other medical and biological fields promises to lead to altered attitudes to existing therapies and the discovery of completely new classes of anti-cancer agents. The next decade should translate into clinical benefit for patients if the progress in this field continues to be as rapid as it has been in the late eighties. We must now determine what characteristics make one tumour more sensitive than another to agents such as heat, PDT, cytokines and FAA, and learn how to extrapolate from those rodent tumours to the human.

Animals↗
PubMed1992

A comparison of vascular-mediated tumor cell death by the necrotizing agents GR63178 and flavone acetic acid.

A vascular component of tumor damage has been identified for the anticancer agent GR63178. The necrotizing activity of this drug and of flavone acetic acid has been compared with their ability to induce growth delay in six murine tumor models. At 24 hr, after a fixed dose of flavone acetic acid (200 mg/kg), all six tumor types appeared 80-100% necrotic histologically, although growth delays ranging from 3 to 79 days were measured. GR63178 (200 mg/kg) induced more variable degrees of necrosis (10 to 95%), but a uniformly small delay in growth (0 to 4 days). These data illustrate that the absence of a tumor-growth response should not be automatically equated with an absence of drug activity. Without assessing tumor response histologically, agents with unusual mechanisms of action may be missed, despite their potential for killing large numbers of tumor cells.

Animals↗
PubMed1992

Inadequate vasculature in solid tumours: consequences for cancer research strategies.

In the last decade, since we first postulated that antiproliferating endothelial therapy was a promising new approach to therapy, there have been remarkable developments. Vascular effects have been recognized from completely unrelated and unexpected agents, including hyperthermia, photodynamic therapy, misonidazole, tumour necrosis factor, FAA, interferon and interleukins. These vascular effects may coexist with direct cytotoxicity to the tumour cells or they may explain all of the antitumour activity. In order to benefit from such vascular effects, we need to monitor them, understand their mechanisms of action and ensure that the clinical scheduling is optimized to give the greatest therapeutic advantage. The biologist must re-evaluate the validity of his or her tumour models and the clinician must question whether drugs targeted at tumour cells should be sought or whether it would be more productive to target the nutrient supply through the neovasculature. The molecular biology approaches of oncogene expression in tumour cells and growth factor dependency must be weighed against angiogenesis, the pathophysiology of the tumour mass and its supporting normal stromal elements. Since this is a highly complex field there will be many fascinating years of work elucidating tumour versus normal vascular differences. In the meantime, we need to ensure that we do not reject useful therapeutic agents by inappropriate scheduling based on a misunderstanding of their mode of action, or by the use of inappropriate models for testing potential anticancer agents.

Antineoplastic Agents↗