In vitro activity of the benzotriazine dioxide SR 4233 against human tumour colony-forming units.
SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a novel bioreductive agent selectively toxic to hypoxic cells. It is active as a radiation sensitiser in vitro. Using a human tumour cloning system we have studied the effects of SR 4233 against freshly explanted human tumour specimens under hypoxic and non-hypoxic culture conditions. For hypoxic conditions, final concentrations of SR 4233 of 10.0-500 mumol/l were used in short-term (1 h) exposure experiments. Final concentrations in non-hypoxic experiments ranged from 10 to 1350 mumol/l. 25 tumour specimens were tested under each culture condition. Of those, 14 (56%) were evaluable. The most common tumour types recruited included ovarian, non-small cell lung, and breast cancer. A moderate concentration-dependent increase in the frequency of inhibited tumour specimens under non-hypoxic conditions was observed with zero out of 10 sensitive specimens at 10 mumol/l as compared with five out of 14 (36%) sensitive specimens at 500 mumol/l (P < 0.02). However, when hypoxic conditions were used SR 4233 had a profound antitumour activity, (two out of 14 specimens sensitive at 10 mumol/l compared with 10 out of 10 specimens sensitive at 500 mumol/l, P < 0.00005). We conclude that SR 4233 is active against tumour colony-forming units in vitro and that its antitumour activity is greatly increased against hypoxic tumour cells.
Hanauske
A R
AR
Technische Universität München, Abteilung Hämatologie und Onkologie, Klinikum rechts der Isar, F.R.G.
Ross
M
M
Degen
D
D
Hilsenbeck
S G
SG
Von Hoff
D D
DD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D010100:Oxygen; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D010100:Oxygen