Using animal models of human breast and prostate cancers, the researchers found that injections of the neurotransmitter dopamine can improve blood flow to tumours and improve delivery of an anticancer drug, doubling the amount of the drug in tumours and increasing its effectiveness. The increased blood flow also raised tumour oxygen levels, a condition that typically improves the effectiveness of both chemotherapy and radiation therapy.
The study also found that dopamine plays an important role in maintaining the structure of normal blood vessels, and that it does this by working through the D2 dopamine receptor, which is present in normal blood-vessel cells called endothelial cells and pericytes. Dopamine was absent in tumour blood-vessel cells.
The findings are published online in the Proceedings of the National Academy of Sciences.
"Our study indicates a use for dopamine in the treatment of cancer and perhaps other disorders in which normalising abnormal and dysfunctional blood vessels might improve therapeutic responses," says principal investigator Dr. Sujit Basu, associate professor of pathology and a researcher in the OSUCCC - James Experimental Therapeutics Program.
"Since dopamine and related agents are already used in the clinic for other disorders, these comparatively inexpensive drugs might be applied to the treatment of cancer to increase the therapeutic responses of chemotherapy and radiotherapy," he says.
The blood vessels that develop inside tumours are structurally abnormal, chaotic and leaky and do a poor job of supplying blood to the tumour, Basu notes. This hinders the delivery of chemotherapeutic agents, and it leaves tumours oxygen deprived. This oxygen deprivation makes tumour cells resistant to chemotherapy and radiation.
Basu and his colleagues found that the dopamine treatment normalises the structure of abnormal tumour blood vessels, indicating an important role for a neurotransmitter in the remodelling of blood vessels.
• The tumour tissue used in the study showed the absence of dopamine.
• After dopamine treatment, tumour blood vessels in both cases resembled normal vessels in regard to leakiness and architecture. Pre-treatment with a dopamine receptor antagonist negated this effect.
• Subcutaneous human colon tumours in mice treated with dopamine and the chemotherapeutic drug 5-fluorouracil (5-FU) accumulated twice the amount of 5-FU as tumours in mice treated with the drug only, and the tumours were less than one-third the size of tumours in mice treated with 5-FU only.
"Overall, our findings suggest that the normalisation of tumour blood vessels using the neurotransmitter dopamine might be an important approach for improving therapeutic efficacy in the treatment of cancer patients," Basu says.
Funding from the National Cancer Institute, US Department of Defence Grant mainly supported this research; a grant from the American Heart Association partially supported one of the investigators.
The other researchers involved in this study were Debanjan Chakroborty, Chandrani Sarkar, Hongmei Yu, Jiang Wang and Zhongfa Liu of Ohio State University; and Partha Sarathi Dasgupta of Chittaranjan National Cancer Institute, Kolkata, India.
The Ohio State University Comprehensive Cancer Centre - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (cancer.osu.edu) strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centred care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centres and one of only seven centres funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 210-bed adult patient-care component, The James is a "Top Hospital" as named by the Leapfrog Group and one of the top 20 cancer hospitals in the nation as ranked by US News & World Report.
Source: Ohio State University
