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Multi-disciplinary team investigates drug transporters during cancer development
On the Path to Perfect Chemotherapy Regimens: Imaging Altered Drug Clearance in Cancer Models using 99mTc-Sestamibi
Using the National Imaging Facility (NIF) node located at the Brain and Mind Research Institute (BMRI), ANSTO LifeSciences and The University of Sydney have formed a multi-disciplinary team to investigate the role of drug transporters during cancer development. The project aims to enable closer monitoring of the response to chemotherapeutic drugs in cancer patients. This will help optimise the drug dose and reduce unwanted side effects.
The Team
Arvind Parmar, Frederic Boisson, Marie-Claude Gregoire, Andrew Katsifis.
ANSTO LifeSciences
John Allen and Graham R. Robertson.
Cancer Pharmacology Unit, ANZAC Research Institute, University of Sydney
Stephen Clarke.
Northern Clinical School, University of Sydney, Royal North Shore Hospital
The Challenges of Chemotherapy
The treatment of cancer patients with drugs is difficult. There is a fine balance between killing tumour cells without damaging normal cells and the body’s clearance of anti-cancer. Anti-tumour action is lost if the drug is cleared too rapidly. Slower metabolism of chemotherapy drugs results in higher concentrations in the body, causing toxicity and the delay or termination of treatment.
One factor known to contribute to altered drug clearance in cancer patients is inflammation associated with the growth of tumours. Professor Graham Robertson says “We have previously found that the presence of a tumour causes a reduction in enzymes and drug transporters in the liver, resulting in slower clearance of drugs”. Because of this effect, some patients develop worse side effects from chemotherapy.
How can molecular imaging help?
To assess the impact of tumour-derived inflammation on the activity of one family of drug transporters, the biodistribution of 99mTc-sestamibi in cancer bearing and non-cancer bearing mice was investigated.
The studies tested the ability of 99mTc-sestamibi to act as a predictive marker for drug clearance and toxicity in normal tissues. The results are expected to clarify the mechanism linking cancer-induced inflammation to reduced drug clearance and provide options for future clinical trials in cancer patients.
The tools
| Imaging System | Inveon Tri-modality PET/SPECT/CT SPECT: 99mTc-60 projection, ROR 30mm, 1 revolution, 15s projection, 20mm travel, 9 x 20mins scan (3hr total scan time) CT: 220° rotation 220 Projection, 4x4 bin, 113.22µm effective pixelsize, 600ms exposure 50kVp, 500µA, 3072x2048, DS1 |
| Animal Model | Balb/cxDBA mice engrafted with Colon 26 (C26) tumour cells Balb/cxDBA healthy normal mice as control group |
| Radiotracer | 30 Mbq/100µl of 99mTc-sestamibi intravenously |
The outcomes
Analysis of the imaging data showed that C26 tumour-bearing mice have slower rates of clearance of 99mTc-sestamibi in kidneys, intestines, gall bladder and liver compared to the control mice.
| Control Mice | Tumoured Mice | |
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| Fig. 1: The increased retention of 99mTc-sestamibi in various organs in tumoured mice compared to normal mice is apparent over 3 hrs. These images have also been used in Siemens latest promotional products. | ||
This finding was supported by biodistribution data where reduced accumulation was evident in intestines, liver, urine and bile fluid in the tumour groups compared to the controls.
The significant differences in 99mTc-sestamibi biodistribution and clearance indicate changes in the activity of transport proteins. These drug transporters make a major contribution to clearance of many anti-cancer agents. This study demonstrates the potential of SPECT imaging with 99mTc-sestamibi for predicting drug clearance and toxicity in humans.
The Future
Based on these results, the team is in the initial stages of understanding how to monitor the clearance of chemotherapeutic drugs. The differences in drug biodistribution and pharmacokinetics for tumour-bearing vs control mice are significant and lay the foundations for subsequent experiments aimed at reversing inflammatory signalling associated with tumoured mice.
We plan to perform imaging with first-line anti-cancer drugs. This will characterise the functional impact of tumour-induced inflammation on anti-cancer drug pharmacokinetics prior to clinical studies. We aim to identify strategies to normalize drug handling, leading to improved individualization of anti-cancer drug dosing.
Progressively, we can establish diagnostic biomarkers to identify patients at greater risk of toxicity from chemotherapy prior to its use. This will enable better surveillance and more appropriate use of prophylactic antibiotics and growth factors. The new knowledge generated from these studies has the potential to fundamentally change cancer chemotherapy dosing strategies and improve the safety and efficacy of cancer treatment.
Publications
Sharma, R., Kacevska, M., London, R., Clarke, S. J., Liddle, C., Robertson, G. Down regulation of drug transport and metabolism in mice bearing extra-hepatic malignancies. British Journal of Cancer, 98, 91–97 (2008).
Boisson, F., Zahra, D., Parmar, A., Gregoire, M-C., Meikle, S., Hamse, H., Reilhac, A. Imaging capabilities of the Inveon SPECT system using single and multi-pinhole collimators. Journal of Nuclear Medicine (submitted 2012)
Project Contacts
Acknowledgement
This study is a component of NHMRC project grant ID#632848 ”Improving the use of chemotherapy” 2010-2012.