Enhancing effect of misonidazole on the response of the RIF-1 tumour to cyclophosphamide

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.

Section: Discussioncontrasting

confidence: 57%

“…At the same time, a number of in vivo studies (Rose et al, 1980, Clement et al, 1980Tannock, 1980;Law et al, 1981;Twentyman, 1981;Martin et al, 1981;Siemann, 1981) have found that administration of MISO to mice at or around the time of cytotoxic drug administration can increase the anti-tumour effect of the cytotoxic drug.…”

mentioning

confidence: 99%

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

Twentyman¹,

Workman²

1983

“…The enhancement of tumour response may be a manifestation of the pre-incubation effects seen in vitro, though alternative mechanisms have been suggested (Law et al, 1981;Workman & Twentyman, 1982). In most instances MISO/cytotoxic-drug combinations show greater effects on tumours than on some normal tissues.…”

Section: Methodsmentioning

confidence: 99%

“…It is known that MISO enhances antitumour activity of various alkylating agents in vivo (Rose et al, 1980;Clement et al, 1980;Tannock, 1980a,b;Law et al, 1981;Martin et al, 1981;Siemann, 1981;Mulcahy et al, 1981;Stephens et al, 1981;Twentyman, 1981). Enhancement of the cytotoxic action of melphalan also occurs in vitro (Stratford et al, 1980;Roizin-Towle & Hall, 1981).…”

mentioning

confidence: 99%

Enhancing effect of pre-treatment of cells with misonidazole in hypoxia on their response to melphalan in air

Smith¹,

Stratford²,

Adams³

1982

Summary.-Pre-treatment of hypoxic cells with misonidazole (MISO) can render these cells more sensitive to a subsequent treatment with melphalan. Results in this paper show that this enhancement (or chemopotentiation) depends on the contact time and concentration of MISO, on the melphalan concentration and also on the cultural history of the cells. Damage due to hypoxic pre-incubation in MISO can be repaired if cells are subsequently aerated at 37°C. In contrast, for cells washed free of MISO and then held under N2 at 37°C, repair is much slower. No repair occurs when cells are held in air at 0°C. The kinetics and extent of repair were dependent on the cells prior culture. Thus for exponential cells repair was complete after %4 h, whereas for plateau -phase cells and cells with prior chronic hypoxia, repair was only partially complete after this time. Dithiothreitol was shown to protect partially against the enhancement of melphalan toxicity. Increased cell killing is also obtained if cells are given high concentrations of MISO (50 mM) in air during exposure to melphalan.

“…ther, pretreatment in vitro of hypoxic cells with misonidazole renders the cells more sensitive to the cytotoxic action of some chemotherapeutic agents (Stratford et al, 1980). Several in vivo studies have shown that MISO apparently potentiates the anti-tumour activity of some chemotherapeutic drugs, particularly alkylating agents, in a variety of experimental tumours (Clement et al, 1980;Rose et al, 1980;Tannock, 1980;Siemann, 1981;Mulcahy et al, 1981;Law et al, 1981;Martin et al, 1981;Twentyman, 1981 (Sheldon & Hill, 1977), by subsequent monolayer cloning (McNally & Sheldon, 1977) and by subsequent soft-agar cloning Clonogenic assay.-Tumour response was assayed by a modification of the soft-agar cloning technique described by Stephens et al (1980). Eighteen hours after treatment, individual tumours were excised, scraped free of muscle, minced with curved scissors, weighed, suspended in 10 ml PBS, 10 mg trypsin and 0 5 mg DNase added, and rotated at 120 rev/min for 20 min in a 37°C chamber.…”

mentioning

confidence: 99%

Potentiation of melphalan activity against a murine tumour by nitroimidazole compounds

Sheldon¹,

Batten²,

Adams³

1982

Summary.-The activity against murine anaplastic MT tumours of the chemotherapeutic agent melphalan, either alone or in combination with one of 6 nitroimidazole compounds, was assayed using an in vivo-in vitro tumour excision assay. The melphalan alone proved cytotoxic to the tumour, whereas relatively little cytotoxicity was produced by any of the nitroimidazoles alone. When the nitroimidazole were given in combination with melphalan, dose-modifying potentiation of its cytotoxicity was observed. Maximum potentiation occurred when the nitroimidazoles were given 0-30 min before the melphalan, although some potentiation was still evident when they were given up to 2 h before or after. There was no threshold in nitroimidazole dose required to produce this potentiation, the degree of potentiation increrasing with dose, albeit at a diminishing rate, to give maximum dose-modification factors of about 3.The 6 nitroimidazole compounds in order of increasing effectiveness as potentiators of melphalan activity were: METRO, Ro 05-9963, MISO, RSU 1047, Ro 03 -8800 and Ro 03 -8799. This order corresponds to the increasing electron affinity of these compounds. The most effective compound here, Ro 03-8799, was about twice as effective as the most widely used nitroimidazole in such studies, MISO.