Potentiation of melphalan activity against a murine tumour by nitroimidazole compounds

Abstract

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.

Radiation sensitization and chemopotentiation: Rsu 1069, a compound more efficient than misonidazole in vitro and in vivo

“…Most of these combination studies have been concerned with MISO. Recently it has been shown that other nitro compounds can show potentiating activity considerably greater than MISO (Workman & Twentyman, 1982;Sheldon et al, 1982). In one of these studies (Sheldon et al, 1982) Appendix RSU 1069 gave satisfactory elemental and mass spectural analyses.…”

“…L MT tumour implanted intramuscularly (Sheldon et al, 1982). This study showed that the compound Ro 03-8799 produced the greatest potentiation.…”

“…with RSU 1069 in saline, and locally irradiated with 230 kV X-rays (Sheldon & Hill, 1977a). Tumour response was determined either by an in vitro soft agar clonogenic assay (Sheldon et al, 1982) or by the probability of local tumour control at 80 days (Sheldon & Hill, 1977b). The soft agar clonogenic assay was also used in the chemopotentiation studies, where male mice bearing the MT tumour were treated i.p.…”

Factors influencing the chemosensitization of melphalan by misonidazole

“…seen in every study: A threshold dose of 300-500mgkg-1 seems to be needed. Only two studies at doses of 500 mg kg-1 or below have demonstrated chemosensitization (Rose et al, 1980;Sheldon et al, 1982) and two other studies have shown no effect at 500mgkg-1 (Fu et al, 1981;Twentyman & Workman, 1982). Far fewer studies have been published using chronic MISO with melphalan.…”

Enhancement of hyperthermochemotherapy for human gastric cancer in nude mice by thermosensitization with nitroimidazoles

“…With regard to the chemosensitizing activity of MISO and MTR (Sheldon et al, 1982;Twentyman & Workman, 1982;Milas et al, 1983), it was observed in in vivo experiments with murine tumours that antitumour drugs, i.e., hydroxyurea, cyclophosphamide, melphalan, adriamycin, etc. had an enhanced effect when given with MISO or MTR, though MTR is less active than MISO (Twentyman & Workman, 1982), while little effect was seen with CDDP, vincristine, 5-FU, and bleomycin.…”