ABSTRACT
Both in vitro and in vivo investigations have shown that cell cycle progression is slowed
or arrested in the G, phase by nitrosoureas such as BCNU and CCNU.37,38.51 Since G,/M cells often are radiation sensitive, it is conceivable that enhanced treatment efficacy could result when nitrosourea-synchronized cell populations are irradiated. Though an intriguing possibility, this synchronization hypothesis for the enhanced cell killing was not borne out in detailed 9L cell culture evaluations which compared the extent of the G, block and degree of potentiation resulting from the nitrosourea-radiation ~ o m b i n a t i o n . ~ ~ . ~ ~ Cell cycle effects may, however, have played a major role in the enhanced tumor control observed when KHT sarcomas were treated with CCNU 24 h prior to r a d i a t i ~ n . ~ , . ~ ~ The cell age response of these two agents in this tumor model are c ~ m p l i m e n t a r y , ~ ~ . ~ ~ ~ ~ suggesting that the potentiated antitumor efficacy may well have been the consequence of cell populations which preferentially survived the nitrosourea treatment, being effectively eliminated by subsequent radiation therapy. 36,54
An alternative mechanism by which nitrosoureas might potentiate X-rays may be through cellular thiol modulations. Nitrosoureas can demonstrate a selective inhibitory effect on the enzyme glutathione red~ctase.~' This inhibition reduces intracellular glutathione (GSH) levels by preventing the recycling of oxidized GSH back to its reduced form. Since the depletion of intracellular thiols may lead to increased radiosen~it ivi ty ,~~,~~ thiol modulation by nitrosoureas could play a part in the observed potentiated cell kill when radiation and nitrosoureas
DAYS POSTIMPLANTATION
are combined. This possiblity seems unlikely to be a major factor, however, since the extent of GSH depletion typically required to observe radiosen~itization~~.~~ far exceeds that expected from therapeutic nitrosourea doses.
