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

Ben Raba, FM

Abstract

This work is concerned with the action of two different anticancer drugs which can
alkylate 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 anticancer
drug. This drug crosses the blood brain barrier and is used routinely for the treatment of
certain types of brain tumours, in particular in childhood malignancies e.g. (cerebellar
astrocytoma, Medulloblastoma).
HPLC studies showed that CCNU and its common metabolites have very high partition
coefficients and are unstable in aqueous solutions. Cytotoxicity studies showed that
both parent compound and metabolites are equitoxic against a number of leukaemic cell
lines (K562, Molt-4, Nalm-6 and Jurkat) and a tumour cell line derived from the central
nervous system (Daoy). Flow cytometry studies showed that the compounds cause cells
to 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 currently
undergoing clinical trials. The activity of RH1 was compared with a new lipophilic ester
derivative of RH1, Es5. It was found using HPLC, Cytotoxicity, comet and flow
cytometry studies that these two quinones behave very similarly in that their cell killing
potencies are enhanced by the presence of the reducing enzyme DT-Diaphorase in the
cells. However we have shown that Es5 has a much higher partition coefficient than
RH1 and yet following cleavage of the ester group produces a quinone whose
Cytotoxicity profile is very similar to RH1. The possibility of using Es5 as an alternative
drug to CCNU is discussed.

• Thesis Type: Thesis
• Deposit Date: Aug 19, 2021
• Additional Information: Funders : Minisitry of Higher Education in Libya;Libyan Embassy in London
• Award Date: Sep 1, 2007