Studies on the mechanism of chemosensitization by misonidazole in vitro

Taylor, Yvonne C.; Bump, Edward A.; Brown, J. Martin

doi:10.1016/0360-3016(82)90717-9

Cited by 29 publications

(9 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…the time of CTX administration with respect to the 16 h MISO regime does not appear to be critical. This is not the result which would have been expected if the in vivo effect were due solely to a progressive depletion of thiols with time and may indicate that a number of contributing mechanisms are involved as found in vitro (Taylor et al, 1982).…”

Section: Discussionmentioning

confidence: 59%

An investigation of the possibility of chemosensitization by clinically achievable concentrations of misonidazole

Twentyman¹,

Workman²

1983

Br J Cancer

View full text Add to dashboard Cite

Summary Experiments have been carried out both in vitro and in vivo to examine the possibility of chemosensitization by misonidazole (MISO) at concentrations which are achievable in the clinic. Using multicellular tumour spheroids in vitro we found that a 16h pre-incubation with 100pgml-1 MISO under hypoxic conditions led to a considerable enhancement of sensitivity to melphalan (MEL) but not to CCNU. Pre-incubation for 16h under hypoxia alone also produced a degree of sensitization to MEL, but there was no effect of oxic pre-incubation with MISO. In vivo experiments using the KHT or RIF-l tumours in C3H mice were designed so that repeated administration of MISO maintained blood concentrations of around 100 gml-l for either 7h or 16h. For the 7h regime, cytotoxic drugs were administered at the 4h point. In most experiments the tumour response to MEL, cyclosphosphamide (CTX), chlorambucil or CCNU was no greater in mice receiving multiple MISO than in mice receiving multiple injections of a balanced salt solution. In the occasional experiment where there was an apparent increase in response, the effect was only small (dose modifying factor <1.5). For the 16 h regime the effect was studied of administering CTX (100mg kg -') at various times during the regime. There was a clear trend towards increased CTX response in mice receiving multiple MISO compared with controls. There was, however, no clear tendency for the effect to increase with length of MISO pre-exposure.

show abstract

Section: Discussionmentioning

confidence: 59%

An investigation of the possibility of chemosensitization by clinically achievable concentrations of misonidazole

Twentyman¹,

Workman²

1983

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…Development of hypoxic cell radiosensitizers thus has a clear rationale; the observations that many of these sensitizers were preferentially toxic to hypoxic cells (Olive & McCalla 1975; Hall & Roizin-Towle 1975;Moore et al, 1976) suggested that they may be complementary to many conventional cancer chemotherapeutic agents, and could thus be used effectively in combination treatments. Indeed, in a number of instances an interaction between the sensitizer and the chemotherapeutic agent was observed (Kelly et al, 1979;Clement et al, 1980;Rose et al, 1980, and reviewed by Siemann, 1984).Many factors have been implicated in the phenomenon of chemosensitization (see Brown 1982, and Siemann 1984 for reviews), including differential toxicity (Kelly et al, 1979), direct interactions between the sensitizer (or its toxic metabolites, which are generally produced under hypoxic conditions) and the chemotherapeutic agent itself (Taylor et al, 1982), alterations of drug pharmacology or delivery (Urtasun et al, 1982;Workman et al, 1983;Lee & Workman 1986), inhibition of repair processes by chemosensitizer treatment (Taylor et al, 1982;Mulcahy 1986), and alterations of cellular drug sensitivity, by, for example, the sensitizer selecting for surviving cells more vulnerable to the chemotherapeutic agent due to cell cycle status or other factors . Perhaps the most consistent observation, however, has been the apparent requirement of hypoxia both in vitro (Brown, 1982;Mulcahy, 1984), and in vivo Wheeler et al, 1984).…”

mentioning

confidence: 99%

“…Many factors have been implicated in the phenomenon of chemosensitization (see Brown 1982, and Siemann 1984 for reviews), including differential toxicity (Kelly et al, 1979), direct interactions between the sensitizer (or its toxic metabolites, which are generally produced under hypoxic conditions) and the chemotherapeutic agent itself (Taylor et al, 1982), alterations of drug pharmacology or delivery (Urtasun et al, 1982;Workman et al, 1983;Lee & Workman 1986), inhibition of repair processes by chemosensitizer treatment (Taylor et al, 1982;Mulcahy 1986), and alterations of cellular drug sensitivity, by, for example, the sensitizer selecting for surviving cells more vulnerable to the chemotherapeutic agent due to cell cycle status or other factors . Perhaps the most consistent observation, however, has been the apparent requirement of hypoxia both in vitro (Brown, 1982;Mulcahy, 1984), and in vivo Wheeler et al, 1984).…”

mentioning

confidence: 99%

Chemosensitization by misonidazole in CCNU-treated spheroids and tumours

Durand

Dj²

1987

Br J Cancer

View full text Add to dashboard Cite

Summary Misonidazole has been demonstrated to enhance the cytotoxicity of several common antineoplastic drugs in vitro and in vivo, and its mechanism of action as a chemosensitizer, though still unknown, is thought to be dependent upon hypoxia. We have used fluorescence-activated cell sorting to evaluate chemopotentiation by misonidazole as a function of cell position in V79 spheroids and KHT tumours. CCNU toxicity was enhanced in all cell subpopulations of both tumours and spheroids, with greater consistency than might be predicted on the basis of the known variations in oxygen tension. Further, both misonidazole and CCNU as single agents were preferentially toxic in the less well oxygenated regions of each system, arguing that differential toxicity canno t be implicated in the chemopotentiation observed. In fact, increased treatment toxicity did not necessarily lead to increased chemopotentiation, nor was potentiation directly related to the metabolism/binding of the misonidazole. Chemopotentiation in multicell systems thus appears to be a complex, multi-factorial process.Hypoxic cells develop spontaneously during the growth of many solid tumours, and are known to be resistant to ionizing radiation and implicated in resistance to several antineoplastic drugs. Clearly, their presence in human tumours may limit the effectiveness of cancer therapy. Development of hypoxic cell radiosensitizers thus has a clear rationale; the observations that many of these sensitizers were preferentially toxic to hypoxic cells (Olive & McCalla 1975; Hall & Roizin-Towle 1975;Moore et al., 1976) suggested that they may be complementary to many conventional cancer chemotherapeutic agents, and could thus be used effectively in combination treatments. Indeed, in a number of instances an interaction between the sensitizer and the chemotherapeutic agent was observed (Kelly et al., 1979;Clement et al., 1980;Rose et al., 1980, and reviewed by Siemann, 1984).Many factors have been implicated in the phenomenon of chemosensitization (see Brown 1982, and Siemann 1984 for reviews), including differential toxicity (Kelly et al., 1979), direct interactions between the sensitizer (or its toxic metabolites, which are generally produced under hypoxic conditions) and the chemotherapeutic agent itself (Taylor et al., 1982), alterations of drug pharmacology or delivery (Urtasun et al., 1982;Workman et al., 1983;Lee & Workman 1986), inhibition of repair processes by chemosensitizer treatment (Taylor et al., 1982;Mulcahy 1986), and alterations of cellular drug sensitivity, by, for example, the sensitizer selecting for surviving cells more vulnerable to the chemotherapeutic agent due to cell cycle status or other factors . Perhaps the most consistent observation, however, has been the apparent requirement of hypoxia both in vitro (Brown, 1982;Mulcahy, 1984), and in vivo Wheeler et al., 1984).In this report, we present data evaluating the cytotoxic effects of misonidazole, MISO, and N-(2-chloro-ethyl)-N'-cyclohexyl-N-nitrosourea, CCNU, singly and in combi...

show abstract

“…These include: alterations in pharmacokinetics and metabolism (Stephens et al, 1981;Tannock, 1980;Clutterbuck et al, 1982), selective toxicity towards hypoxic or non-cycling cells (Sutherland, 1974), the generation and fixation of free-radical intermediates (Clement et al, 1980), inhibition of the repair of potentially lethal damage (PLD) (Law et al, 1981;Martin et al, 1981;Siemann & Mulcahy, 1982), or reduced levels of intracellular sulphydryl-containing compounds such as glutathione (GSH) (Taylor et al, 1982a;Roizin-Towle et al, 1982) which are involved in detoxification of electrophilic drugs such as MEL and are also free-radical scavengers. Although hypoxia is a prerequisite for in vitro sensitization (Stratford et al, 1980;Roizin-Towle & Hall, 1981), its exact significance in terms of normal tissue versus tumour toxicity in vivo is unclear (Tannock, 1980;Law et al, 1981).…”

mentioning

confidence: 99%

“…Since MISO is known to deplete intracellular levels of GSH in hypoxic cells (Varnes et al, 1980;Taylor et al, 1982a), we also investigated the possible involvement of glutathione in chemosensitization. Both DEM and MISO did cause a significant alteration of GSH levels ( Figure 5), but this was tissue specific and possibly related to the requirement of hypoxia for MISO but not for DEM to deplete GSH in vitro (Varnes et al, 1980).…”

mentioning

confidence: 99%