There is an emerging trend towards following similar practices for the management of low-grade gliomas in Europe. Our results are descriptive and formalise current discussions in our group. Also, they contribute towards the development of a European assessment protocol.
Summary The vaso-active drug hydralazine causes a considerable increase in the cytotoxic effect of melphalan towards the KHT tumour in mice. The enhancement in response, measured as the concentration of melphalan required to achieve a given tumour response, is 3.0 and 2.35 when determined using the regrowth delay assay and the technique for determining surviving fraction in vitro following treatment in vivo respectively. In contrast, measurement of systemic toxicity shows that the addition of hydralazine only causes a small increase (ER= 1.15) in melphalan damage. This suggests that the drug combination may have some therapeutic benefit. The tumour specificity for the action of hydralazine is supported by the finding that binding of 3H-misonidazole is increased in tumours but not in other tissues when mice are treated with hydralazine. Increased binding of labelled misonidazole is associated with an increase in the level and duration of hypoxia, which will occur as a consequence of changes in tumour blood flow brought about by hydralazine. However, hypoxia per se is not responsible for the enhanced effect of melphalan, since the agent BW12C, which also induces substantial tumour hypoxia as a result of changing the 02 affinity of haemoglobin, has no effect on melphalan tumour cytotoxicity.There have been various reports showing that vasoactive drugs can significantly affect the nature of blood flow in both experimental rodent and human tumours (Algire & Lagallais, 1951;Cater et al., 1962;Kruuv et al., 1967; Vorhees & Babbs, 1982;Knapp et al., 1985). Reduced blood flow in tumours can cause lowering of the oxygen status of the tumour, thereby causing radiation resistance (Kruuv et al., 1967). This so-called 'stealing' effect has recently been exploited by Chaplin and Acker (1987) in order to increase the anti-tumour effect of the bio-reductive agent, RSU 1069 (Adams et al., 1984) a compound which is activated under hypoxic conditions to give a species 100 x more toxic than the parent compound (Stratford et al., 1986).Reduction of blood flow in tumours may also be potentially useful for enhancing the effects of some anti-cancer drugs. The rationale for this is that, administration of the vaso-active drug at the time at which the chemotherapeutic agent has reached its maximum tumour concentration, will inhibit loss of active drug from the tumour. This could increase the overall exposure of the tumour cells to the cytotoxic drug. This paper describes the results of a study of the effect of the vasoactive agent hydralazine on the cytotoxic action of melphalan (L-phenylalanine mustard, L-PAM) towards the KHT sarcoma in mice. Materials and methodsMice and tumours Eight to 12 week old male Category IV C3H/He mice, obtained from NIMR, Mill Hill, London in 1984 and subsequently bred 'in-house', were used in the present experiments. The KHT sarcoma (Kallman et al., 1967), provided by Dr P. Twentyman, MRC, Cambridge in 1983, was maintained by inoculation of a tumour brei into the gastrocnemius muscle of female mice. Generall...
The response of the intra-arterial pressure to the cold immersion stimulus was studied in 42 healthy young adults, continuous direct (arterial-pressure) recording being used. The average systolic elevation was 22.6 mm. Hg and the average diastolic elevation was 16.3 mm. Hg. The difference between direct and indirect methods of measuring blood pressure was studied in 351 simultaneous determinations in 35 of these young adults. The direct systolic pressure averaged 9.7 mm. Hg higher and the diastolic pressure was 7.3 mm. Hg lower than the indirect measurement.T HE cold pressor test of Hines and Brown1 has been used widely during the past 22 years in the study of essential hypertension2-9 and the toxemias of pregnancy.'0 11 Up to the present, exact knowledge of the nature and significance of the cold pressor response has been limited by the intermittent measurements possible with the sphygmomanometer. However, now that continuous direct recording of arterial pressure is established as an accurate and reliable laboratory procedure, a new tool is available for the study of the cold pressor test.The response of the intra-arterial pressure to the cold immersion stimulus (4 C. for 60 seconds) was studied in 42 healthy young adults, continuous direct arterial pressure recording being used. The cold pressor test of Hines and Brown was applied repeatedly at short intervals, and the direct record was examined with regard to (1) maximal elevation of pressure, (2) time required to reach the maximal pressure and (3) time needed to return to one half the maximal pressure (the last figure was taken as a measure of the recovery time). The difference between the direct and
It is known that hydralazine can decrease blood flow to experimental murine tumours. A consequence of this, in the KHT sarcoma, is the induction of close to 100 per cent radiobiological hypoxia, which lasts for nearly 2 h following i.v. injection of 5 mg/kg hydralazine to the mouse. This phenomenon is exploitable in order to increase the apparent sensitizing efficiency of the nitroheterocyclic radiosensitizers, misonidazole and RSU 1069, and is demonstrated using the treatment schedule: sensitizer----60 min----X-rays----1 min----hydralazine. Such a strategy will first take advantage of the radiosensitizing properties of the nitroimidazole, then after irradiation the hydralazine should allow expression of the differential toxicity towards hypoxic cells known to occur with misonidazole and RSU 1069. Misonidazole gives an enhancement ratio (ER) of 1.3 at 100 mg/kg, rising to 2.0 at 1000 mg/kg. Where hydralazine is given after irradiation, no additional cell kill is observed with 1000 mg/kg. In contrast, at lower doses of misonidazole, hydralazine induces a substantial increase in cell killing such that the ER obtained with 100 mg/kg is the same as that achieved with 1000 mg/kg misonidazole when used alone with radiation. Similarly, 20 mg/kg RSU 1069 with radiation followed by hydralazine is equivalent to the radiosensitizing effect of 80 mg/kg RSU 1069 without hydralazine. In addition, doses of RSU 1069 that normally give no radiosensitization (5 or 10 mg/kg) produce substantial increases in cell killing when combined with hydralazine.
Summary We have investigated the cross-sensitivity of a number of cell lines to three different classes of bioreductive drugs under both aerobic and hypoxic conditions. The cell lines used were selected for their sensitivity to DNA-damaging agents and fall into two groups. One group, MMC cells derived from CHO-KI cells (Robson et al., 1985), show a range of sensitivities to mitomycin C in air. The second group, irs cells were cloned from V79 Chinese hamster fibroblasts (Jones et al., 1987) and exhibit sensitivity to ionising radiation. The sensitivity of both groups of cells to mitomycin C (MMC), RSU-1069 Hypoxic cells within tumours are known to limit the efficacy of radiotherapy. Bioreductive and radiosensitising drugs are under development in order to improve tumour therapy by sensitising the hypoxic tumour cells to either radiation or cytotoxic chemotherapy. One process by which hypoxic cells can be selectively killed is to utilise the reductive metabolic pathways which can be exploited readily under poorly oxygenated conditions.The mechanism of action of three different classes of bioreductive compounds have been investigated in vitro, using cell lines selected for their sensitivity to DNA damaging agents. The drugs investigated were the bioreductive quinone antibiotic mitomycin C (Kennedy et al., 1980); a monofunctional alkylating 2-nitroimidazole RSU-1069 (Adams et al., 1984;Stratford et al., 1986); and the benzotriazine-di-N-oxide SR4233 (Zeman et al., 1986(Zeman et al., , 1989.The cell lines used fall into two groups, both of which were cloned from Chinese hamster cell lines. The first, MMC cells, were isolated from Chinese hamster ovary cells, CHO-K1 (Robson et al., 1985), and were either hypersensitive (MMC-2 and MMC-3), or resistant (MMCl) to mitomycin C. The concentrations of MMC required to reduce cell survival to 0.37 of the control following 24 hour aerobic exposure (D37 value) have been determined by Robson et al. (1985) and Hoban et al. (1990) for each cell line. These are: CHO-KI, 0.32; MMC-2, 0.05; MMC-3, 0.07; MMCr, 6.07,UM respectively. The second group of cells, irs cells were originally cloned from V79 Chinese hamster fibroblasts (Jones et al., 1987) and exhibit a range of sensitivities to ionising radiation in air. For these cell lines D37 values (Gy) have been determined as; V79, 4.2; irs 1, 1.34; irs 2, 1.41; irs 3, 2.06 (Jones et al., 1987).The cross-sensitivity of these cell lines to MMC, RSU-1069 and SR4233 has been assessed under both hypoxic and aerobic conditions. This type of study may help to determine the mechanism of action of these agents and the factors influencing cellular sensitivity to bioreductive cytotoxic drugs, in particular the enzymes involved in drug activation and cellular repair pathways. gassed with N2 + 5% CO2 at 37°C for 3 h. The drug-containing medium was then removed from the dishes, replaced with fresh medium and cells assayed 7-10 days later for colony formation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.