Selected Bibliography

• Christlieb Martin, Cowley Andrew R, Dilworth Jonathan R, Donnelly Paul S, Paterson Brett M, Struthers Harriet SR, and White Jonathan M (2007) New bimetallic compounds based on the bis(thiosemicarbazonato) motif. Dalton Trans(3):327-31.

• Christlieb Martin, Struthers Harriet SR, Bonnitcha Paul D, Cowley Andrew R, and Dilworth Jonathan R (2007) The exocyclic functionalisation of bis(thiosemicarbazonate) complexes of zinc and copper: the synthesis of monomeric and dimeric species. Dalton Trans(43):5043-54.

• Folkes Lisa K, Christlieb Martin, Madej Edyta, Stratford Michael RL, and Wardman Peter (2007) Oxidative metabolism of combretastatin A-1 produces quinone intermediates with the potential to bind to nucleophiles and to enhance oxidative stress via free radicals. Chem Res Toxicol, 20(12):1885-94.

• Holland Jason P, Aigbirhio Franklin I, Betts Helen M, Bonnitcha Paul D, Burke Paul, Christlieb Martin, Churchill Grant C, Cowley Andrew R, Dilworth Jonathan R, Donnelly Paul S, Green Jennifer C, Peach Josephine M, Vasudevan Sridhar R, and Warren John E (2007) Functionalized bis(thiosemicarbazonato) complexes of zinc and copper: synthetic platforms toward site-specific radiopharmaceuticals. Inorg Chem, 46(2):465-85.

• Pascu Sofia I, Waghorn Philip A, Conry Timothy D, Betts Helen M, Dilworth Jonathan R, Churchill Grant C, Pokrovska Tzveta, Christlieb Martin, Aigbirhio Franklin I, and Warren John E (2007) Designing Zn(II) and Cu(II) derivatives as probes for in vitro fluorescence imaging. Dalton Trans(43):4988-97.

Dr. Martin Christlieb

As tumours grow, they can suffer from an inadequate blood supply leading to areas with low oxygen levels.  The cells adapt to this shortage as best they can; unfortunately, many of the adaptations also give rise to increased tumour aggression and invasiveness.  Simultaneously, the presence of hypoxia brings resistance to chemo- and radio-therapy.  This is an unhealthy combination and can be the difference between life and death for the patient.  An accurate, non-invasive and quantifiable method of assessing tumour oxygenation would help medics deliver the correct treatment regime.  Two promising imaging techniques are PET and SPECT.  These rely on delivery of a radio-isotope selectively to the hypoxic tissues so that the presence and extent of hypoxia can be visualised and measured.

Chemistry

New molecules which have the required biological selectivity and carry a suitable gamma-(SPECT) or positron-(PET) emitting isotope must be made.  We closely collaborate with (Prof. Jon Dilworth) and (Dr. Veronique Gouverneur) of the Department of Chemistry.  We are interested in developing new tracers based on fluorine-18 and radioactive copper isotopes.  Fluorine is the mainstay of PET imaging and the isotope is widely available, while copper chemistry can be fast, quantitative and amenable to the non-expert.  One copper based imaging agent that has received a lot of attention recently is Cu[ATSM].  As part of our chemistry research we are hoping to improve the properties, broaden the scope of the compound to include radio-therapy and detail procedures for radio-labelling which can be carried out without a dedicated hot-lab or any specialist training in chemistry.

Cu[ATSM] and a new structural analogue with greatly improved solubility.

Biology

New agents and exciting chemistry are of little value if there is no biological feedback to assess the properties of these new agents.  We are working with collaborators in biological sciences (Dr Grant Churchill) and physical sciences (Prof. Boris Vojnovic) to gather information on the cellular behaviour of new complexes using traditional fluorescence microscopy techniques.  This information can then be used to help inform the selection of future synthetic targets.

Analogues of Cu[ATSM] fluoresce and might give us important biological data.

In vivo PET

In vitro experiments can tell us how a compound behaves in the confines of a single cell, but in a patient the compound must survive long enough to get to the site of interest, must be transported to the site and must be absorbed into the tumour as it passes in the blood stream.  We use various tumour strains in rat and mouse models to obtain information on the biodistribution and pharmacokinetics of our compounds as well as checking for the oxygen dependant accumulation.

New imaging methods – nanoSIMS

Fluorescence work is done with large molecules tagged with fluorophores or fluorescent secondary antibodies.  Our tracer molecules are small, typically 300-600 amus.  Attachment of a fluorescent probe would almost certainly alter the biological behaviour.  An alternative method would be to look for isotopes unique to our tracer and not found naturally in the cell.  Small molecules can be labelled with stable isotopes such as deuterium without altering the biological properties.  A technique known as nanoSIMS is able to look for these artificial mass fragments in a cell with 50 nm resolution.  By labelling our proposed tracers and correctly preparing the cell samples we are developing this technique as an alternative to fluorescence microscopy.  This work is in collaboration with Prof. Chris Grovenor of the materials department.

An image of BrdU within a cell nucleus.

Image analysis

In conjunction with Prof. Sir Mike Brady we are developing methods for automatically analysing image data.  The current project automatically segments brightfield microscopy data and uses the resulting cell outlines to quantify fluorescence data acquired from the cells.  Projects in the near future include analysis of PET data to understand distribution and kinetics according to compartmental models.

Cells are automatically segmented by in-house software.

1992 - 1998 MA and PhD
University of Cambridge

1999 Post-doctoral work
Stanford University

2000-2002 Post-doctoral work
Organic Chemistry
University of Oxford

2002-2005 Post-doctoral work
Inorganic Chemistry
University of Oxford

2006-present Gray Cancer Institute
Radiation Oncology and Biology
University of Oxford