Enhancement of the action of alkylating agents by single high, or chronic low doses of misonidazole

Summary The effects of single doses of misonidazole (MISO) on blood flow and vascular volume in the SaFA and CaNT tumours and normal tissues of the mouse have been studied. MISO was administered in the dose range 250-1,000mg kg-and blood flow measured at different times after MISO by the 86RbCl extraction technique. Vascular volume was assessed by the distribution of 51Cr-labelled red blood cells. MISO at doses of 500 mg kg -or greater decreased flow in both tumours by up to 60% within 2 h. Flow remained reduced for up to 24 h. Similar but less profound changes were seen in the skin, although flow had recovered by 24 h. Only slight changes were seen in muscle, and none in kidney. The apparent loss of flow in tumours seen after large single doses of MISO may have important implications for its use as a chemosensitizer.Misonidazole (MISO), a hypoxic cell radiosensitizer in vivo and in vitro Fowler et al., 1976) can also act as a chemosensitizer, potentiating the effects of various chemotherapeutic agents (McNally, 1982;Millar, 1982;Siemann, 1984). In a recent study of the effects of MISO combined with melphalan on the vasculature of a murine sarcoma (Murray et al., 1987) we presented evidence that this combination of drugs profoundly affected vascular structure and function at doses which in combination produced significant growth delay. Our results, obtained using a fluorescent dye (Hoechst 33342) perfusion technique, indicated that MISO alone might be largely responsible for these vascular effects. We have therefore examined the effects of MISO on vascular function in the same tumour model using alternative techniques to measure both vascular volume and blood flow. The aim of these studies was to (a) corroborate our earlier observations, (b) determine the time course and dose-dependence of these effects, and (c) extend these studies to another tumour. In addition we have compared the effect on the sarcoma with that on several normal tissues, in an attempt to determine whether the observed effects were the result of a direct action on the tumour vasculature, or of a more general physiological effect. Materials and methods TumoursThe SaFA sarcoma was transplanted by trocar as 1 mm3 pieces subcutaneously onto the backs of WHT/Gy f BSVS mice. The anaplastic carcinoma CaNT was transplanted s.c. on to CBA/Ht Gy f TO mice by injection of a cell suspension in saline, obtained by mechanical disruption of a tumour. Drug treatmentMisonidazole (MISO, Roche Ltd), was administered by i.p. injection of a solution of the drug dissolved in sterile saline at a series of concentrations representing total doses ranging from 250-1,000omgkg-1 Vascular perfusion estimated by Hoechst 33342 Vascular perfusion of the SaFA tumour was assessed at different times (2, 12 and 24 h) after MISO treatment. One minute before sacrifice, tumour-bearing mice were injected intravenously with the fluorescent DNA-binding dye Hoechst 33342, dissolved in saline to a concentration of 4 mg ml -1, and administered at a dosage of 40 mg kg-1 (Murray et al., 1...

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Misonidazole reduces blood flow in two experimental murine tumours

Randhawa²

1988

“…It is then a simple matter to determine that a lOx increase in mean plasma concentration of sensitizer achieves a 4x decrease in cell survival or that a lOx decrease in cell survival results from a 46x increase in sensitizer concentration. The existence of a threshold dose which must be achieved before measurable enhancement occurs has been proposed (McNally et al, 1983) to account for differing results with low levels of sensitizer from various laboratories. Our data do not support this.…”

Section: Discussionmentioning

confidence: 99%

“…In general, there is agreement that the largest enhancements are seen when nitroimidazoles, particularly misonidazole (MISO), are combined with compounds having bifunctional alkylating activity. There is evidence that at least part of this effect for some of these alkylating agents can result from altered pharmacokinetics of the agent (Hinchcliffe et al, 1983;Lee & Workman, 1983), but it seems likely that other mechanisms exist to explain the relative sparing of normal tissues reported in many studies. In particular, the hypoxia-mediated enhancement of the formation of DNA interstrand crosslinks seen in vitro (Taylor et al, 1983) is a particularly attractive explanation of this tumour selectivity.…”

mentioning

confidence: 99%

Sensitization of normal and malignant tissues to cyclophosphamide by nitroimidazoles with different partition coefficients

Hirst¹,

Hazlehurst²,

Brown³

1984

Summary The ability of a range of 2-nitroimidazoles with similar electron affinities but widely differing partition coefficients (P) to enhance the cytotoxicity of cyclophosphamide (CY) in mouse tumour and normal tissues was investigated. In a preliminary study large single doses of benznidazole (BENZ), misonidazole (MISO), desmethylmisonidazole (DMM), and SR-2508 were found to give similar enhancement of the RIF-I and SCC VII/St tumours. SR-2555 was less effective. A direct comparison was made between MISO and SR-2508 using prolonged, low-level drug exposures, achieved by multiple injections. The enhancement of CY cytotoxicity achieved in the two tumour systems (RIF-l and SCC VII/St) was found to be similar for a given blood sensitizer concentration. In the normal tissue assays (white blood cell count, bone marrow CFU-S and testis spermatogonia) neither MISO nor SR-2508 produced significant enhancement of CY cytotoxicity, so that the therapeutic gains achieved at a given blood concentration of sensitizer were similar for SR-2508 and MISO. The main advantage of SR-2508, however, will probably lie in its lower toxicity, permitting higher blood levels to be achieved. However, the slope of the dose response curves are rather shallow so we would not predict a dramatically increased benefit.

“…These single dose studies are difficult to translate directly into clinical terms, because of the 10-fold difference between mouse and man in the half-life of MISO, particularly since the cytotoxic effect to MISO is reported to be a supralinear function of exposure time (Hall et al, 1978;Stratford & Adams, 1978). A few murine studies have been reported in which the human pharmacokinetics with lower plasma levels of MISO have been simulated by multiple injection schedules in order to assess the possible role of chemosensitization by MISO in the clinic (Hirst & Brown, 1982;McNally et al, 1983;Twentyman & Workman, 1983). Some of these studies have demonstrated significant chemosensitization, but it is not a universal finding.…”

mentioning

confidence: 99%

Factors influencing the chemosensitization of melphalan by misonidazole

Randhawa¹,

Stewart²,

Denekamp³

et al. 1985

Summary The effect of melphalan alone or combined with various schedules of misonidazole (MISO) has been tested on a murine fibrosarcoma. The tumoricidal effect has been determined using the growth delay assay. Large single doses (500-1000mg kg-1) of MISO enhanced the anti-tumour effect of melphalan, especially at high melphalan doses. This was accompanied by a drop in body and tumour temperature and an increase in the melphalan half-life. The MISO-induced hypothermia was prevented in one experiment by keeping the mice in an ambient temperature of 35°C for 3 h. This reduced the exposure to melphalan but did not diminish the cytotoxic effect of the drug combination.Chronic administration of MISO for an 8h period gave no enhancement of melphalan damage, whether melphalan was given half-way through or at the end of the period of dosing. It seems that a threshold tumour concentration of MISO, in excess of 70 pg g-, is needed for enhancement of melphalan cytotoxicity; prolonged exposures to very low doses are ineffective.