Group Leader:
Geoff Margison
I first joined the Department of Chemical Carcinogenesis at the (then) Paterson Laboratories, in 1966 as a research technician. In 1967, I went to Manchester University, obtained a BSc degree and then returned to the Paterson to undertake a Ph.D. studying the biochemical effects of chemical methylation of DNA. I obtained my Ph.D. in 1973. My first postdoctoral fellowship was at the Max-Planck Institute for Brain Research in Cologne, Germany, between 1973-1975, before accepting a visiting fellowship at the International Agency for Research on Cancer in Lyon, France. I rejoined the Cancer Research Campaign Carcinogenesis Department (which became Cancer Research UK Carcinogenesis Group), at the Paterson in 1976. I was awarded a tenure in 1978, a Special Appointment in 1992 and since 1997 have been Group Leader.
Postdoctoral Fellow
Vitaly Latypov
Scientific Officers
Mandy Watson
Gail McGown
Mary Thorncroft
Graduate Student
Andrew Marriott
Carcinogenesis Group - DNA damage and repair in chemotherapy
Alkylating agents of various types are used alone or in combination with other agents in the treatment of many cancer patients. Their effectiveness is limited by adverse toxic side effects in normal tissues, which defines the maximum tolerated doses, and by the inherent or treatment-induced resistance of the tumour to therapy.Until improved therapeutic agents that circumvent these problems are developed, the only option for better patient management is to establish the mechanisms of tumour resistance and normal tissue sensitivity of currently used agents and then to devise strategies to improve in their effectiveness. Extensive studies of the DNA damaging, carcinogenic and toxic properties of these agents has provided sufficient insight into their mechanisms of action to devise and test such strategies.
Chemotherapeutic alkylating agents attack DNA bases at some twelve different sites
Chemotherapeutic alkylating agents attack DNA bases at some twelve different sites and there is increasing understanding of the biological effects of some of these lesions and the repair systems that can process them (see above). Thus methylating agents such as DTIC (Dacarbazine) and the CR-UK drug, Temozolomide (which is marketed by Schering-Plough as Temodar) produce O6-methylguanine in DNA and this kills cells via the action of the post replication mismatch repair (MMR) system.
Pathways for the biological effects of O6-methylguanine generated in DNA by methylating agents such as Temozolomide, and damage reversal by MGMT. The mechanism of DNA interstrand crosslinking by BCNU and related chloroethylating agents is shown on the right.
Chloroethylating agents such as BCNU (carmustine) produce O6-chloroethylguanine and this alkylating kills cells via DNA interstrand crosslinks. Methylating and chloroethylating agents are often referred to as 'O6-alkyalting' agents because it is considered that the major toxic lesion generated in DNA by these agents is O6-alkylguanine. Although other toxic and mutagenic lesions are, as described above, well defined, their contribution to the overall biological effects of these agents is still being established.