Mechanistic studies on aziridinylbenzoquinones and CCNU [l-(2-chloroethyl)- 3-cyclohexyl-l-nitrosourea] in cultured tumour cells

This work is concerned with the action of two different anticancer drugs which canalkylate DNA in tumour cells.The first alkylating agent studied was CCNU [(l-(2-chloroethyl)-3-cyclohexyl-lnitrosourea,Lomustine]. This is a well established clinically used lipophilic anticancerdrug. This drug crosses the blood brain barrier and is used routinely for the treatment ofcertain types of brain tumours, in particular in childhood malignancies e.g. (cerebellarastrocytoma, Medulloblastoma).HPLC studies showed that CCNU and its common metabolites have very high partitioncoefficients and are unstable in aqueous solutions. Cytotoxicity studies showed thatboth parent compound and metabolites are equitoxic against a number of leukaemic celllines (K562, Molt-4, Nalm-6 and Jurkat) and a tumour cell line derived from the centralnervous system (Daoy). Flow cytometry studies showed that the compounds cause cellsto arrest in the G2-M phase of the cell cycle and can also induce apoptosis.The second alkylating agent studied was RH1 (2, 5-diaziridinyl-3 -hydroxymethyl-6-methyl-1, 4-benzoquinone) which is a novel water soluble prodrug which is currentlyundergoing clinical trials. The activity of RH1 was compared with a new lipophilic esterderivative of RH1, Es5. It was found using HPLC, Cytotoxicity, comet and flowcytometry studies that these two quinones behave very similarly in that their cell killingpotencies are enhanced by the presence of the reducing enzyme DT-Diaphorase in thecells. However we have shown that Es5 has a much higher partition coefficient thanRH1 and yet following cleavage of the ester group produces a quinone whoseCytotoxicity profile is very similar to RH1. The possibility of using Es5 as an alternativedrug to CCNU is discussed.

Level dc:type.qualificationlevel

Doctoral (Level 8)

Year dc:date.issued

2007

Author dc:creator

• Ben Raba, FM

Language dc:language

en

Identifier

oai:salford-repository.worktribe.com:1336991

OAI identifier oai:identifier

oai:salford-repository.worktribe.com:1336991