Misonidazole Cytotoxicity in Vivo: A Comparison of Large Single Doses with Smaller Doses and Extended Contact of the Drug with Tumor Cells

Conroy, Peter J.; Sutherland, Robert M.; Passalacqua, W

doi:10.2307/3575268

Cited by 11 publications

(4 citation statements)

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“…It has been shown (Moore et al, 1976) that both contact time and drug concentration influence the hypoxic cell cytotoxicity of MISO in vitro. Conroy et al (1980) showed that prolonged exposure in vivo to MISO alone at levels similar to those used in the present study reduced the surviving fraction of EMT6/Ro cells to 0-5. However, no cytotoxicity was observed in the EMT6/St/lu tumour after prolonged exposure to low MISO levels (achieved by nephrectomy) in the mouse (Brown & Yu, 1979) and, as can be seen in Figs 1, 3 & 4, no effect of multiple MISO alone was seen in the RIF-1 tumour in the present study.…”

Section: Discussionmentioning

confidence: 75%

Effect of clinical levels of misonidazole on the response of tumour and normal tissues in the mouse to alkylating agents

Brown¹,

Hirst²

1982

Br J Cancer

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Summary.-Experiments were carried out to determine whether the enhancement of alkylating-agent cytotoxicity seen after large single doses of misonidazole (MISO) in mouse tumours can also be achieved by prolonged exposure to low MISO levels similar to those which can be tolerated clinically.The level in mouse blood plasma could be maintained at about 100 jig/ml for 7 h by injecting small doses of MISO every 1/2 h. The effect of this treatment in combination with cyclophosphamide (CY) or melphalan (L-PAM) was studied in the RIF-1 tumour, using regrowth delay and cell-survival cloning assays. In each case, prolonged exposure to low levels of MISO gave enhancement ratios very close to those obtained with a large single dose. ERs of 16-2-0 were obtained with CY and 18-2.2 with L-PAM over the range of alkylating-agent doses used.In experiments with CY the response of 2 normal-tissue systems, marrow and WBC count, was also studied. No significant enhancement of CY damage occurred in either case. In the L-PAM experiments the LD50/30 and WBC counts were determined as normal-tissue end points. Multiple MISO had no effect.Our results show that levels of MISO which can be achieved safely in man yield good enhancement of the tumour cytotoxicity of 2 widely used chemotherapeutic agents without increasing the damage to normal tissues.

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Section: Discussionmentioning

confidence: 75%

Effect of clinical levels of misonidazole on the response of tumour and normal tissues in the mouse to alkylating agents

Brown¹,

Hirst²

1982

Br J Cancer

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“…the peak concentration achievable, chemosensitization depends on concentration and the overall exposure time, since by extending the exposure to a low plasma level of MISO for a long time it is possible to achieve chemosensitization which would not be seen if the same plasma level were achieved following a single MISO dose. The hypoxic cell toxicity of MISO in vitro also depends on concentration and contact time (Moore et al, 1976), and Conroy et al (1980) have shown significant tumour cytotoxicity of MISO following i.v. infusion at a variable rate to simulate human pharmacokinetics.…”

Section: Discussionmentioning

confidence: 99%

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

McNally¹,

Hinchliffe²,

Ronde³

1983

Br J Cancer

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“…Mitomycin C, although exhibiting preferential cytotoxicity to hypoxic cells in vitro, fails to show selective cytotoxicity for hypoxic cells in vivo (Rauth et al, 1983;Rockwell & Kennedy, 1979). Misonidazole and other hypoxic cell sensitizers, although showing preferential cytotoxicity to hypoxic cells in vivo, do so only at drug concentrations well above those which can be given clinically (Brown, 1977;Conroy et al, 1980).…”

Section: Introductionmentioning

confidence: 99%

Effect of Coccinia indica on Blood Glucose, Insulin and Key Hepatic Enzymes in Experimental Diabetes

Jagetia

Nayak

Vidhyasagar

2002

Pharmaceutical Biology

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The radiosensitizing effect of various guduchi (Tinospora cordifolia Miers, Menispermaceae) extracts, i.e., pretreatment with 10 mg/ml of methanol (Met), aqueous (Aqu) or methylene chloride (Mch) extracts, was studied in the HeLa cells exposed to 0, 0.5, 1, 2, or 3 Gy of g-radiation. The irradiation of cells resulted in a dose-dependent decline in the clonogenicity of cells expressed as reduction in cell survival. Treatment of HeLa cells with Met, Aqu or Mch extract before exposure to different doses of g-radiation resulted in a significant decline in the cell survival when compared with the phosphate-buffered saline (PBS) + irradiation group. The highest loss in the clonogenicity was observed in Mch + irradiation group, where the cell survival was lower than doxorubicin (Dox) + irradiation group. Conversely, the frequency of micronuclei increased in a dose-dependent manner in all the groups and a significant elevation in micronuclei frequency was observed in Met + irradiation, Aqu + irradiation, Mch + irradiation and Dox + irradiation groups relative to the PBS + irradiation group. The dose enhancement factor for micronuclei-induction varied between 1.4 to 1.97, depending on the type of extract and dose of irradiation. The dose response for all the groups was linear quadratic. The biological response was determined by plotting the surviving fraction of cells versus micronuclei frequency, respectively, for all the groups. The correlation between cell survival and micronuclei-induction was found to be linear quadratic for all the groups. In spite of a good correlation between micronuclei frequency and cell survival, the frequency of micronuclei was lower in Mch + irradiation group than in the other two groups (i.e., Met and Aqu), owing to the greater cell kill as evidenced by the higher decline in the cell survival in this group when compared to the other groups. However, the statistical difference among all guduchi extracts pretreated groups was not significant. The present study demonstrates that all the guduchi extracts were able to enhance the effect of radiation significantly. However, the most effective extract was Mch, where the reduction in the surviving fraction of cells was higher than either Aqu + irradiation, Met + irradiation or Dox + irradiation group.

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Misonidazole Cytotoxicity in Vivo: A Comparison of Large Single Doses with Smaller Doses and Extended Contact of the Drug with Tumor Cells

Cited by 11 publications

References 0 publications

Effect of clinical levels of misonidazole on the response of tumour and normal tissues in the mouse to alkylating agents

Effect of clinical levels of misonidazole on the response of tumour and normal tissues in the mouse to alkylating agents

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

Effect of Coccinia indica on Blood Glucose, Insulin and Key Hepatic Enzymes in Experimental Diabetes

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