application: The extracellular pH (pHe0 of solid tumors is significantly and consistently more acidic than that of normal tissues. This is an important problem because acidic pH is mutagenic and clastogenic, induces expression of growth factors, activates protooncogenes, increases invasion and metastasis, and enhances resistance to radio- and chemotherapies. The long term goal of this work is to gain a mechanistic understanding of the processes that establish this acid pH and the pathophysiological consequences of chronic acidity which are germane to the cancerous phenotype. The shorter term goals outlined in this proposal are to improve methods to measure pHe in vivo, to better understand how this acidic pHe is established and maintained, and to determine the effects of acidic pHe on response of breast cancer tumors to chemotherapy. This latter consequence of pH is well established in vitro and in theory yet, until recently, there was a lack of in vivo verification.
Aim 1 proposes to improve measurements of pHe values in tumors using magnetic resonance spectral imaging (MRSI) of derivatized imidazoles. This approach has generated the first-every """"""""pH maps"""""""" of living tissue. These pH maps will be compared to tumor morphology and local physiology to better understand how tumor pHe is regulated.
Aim 2 will investigate the regulation of pHe by determining the effect of tumor blood flow (TBF) on the pHe, the intracellular pH (pHi) and the lactate levels in MCF-7 breast cancer tumors, and in tumors of MCF-7 cells which have been genetically engineered to have altered pHe and pHi.
Aim 3 will investigate how low pHe affects the sensitivity of tumors to ionizable chemotherapeutic agents. This will be investigated by reversibly altering the pHe during the course of chemotherapy. pHe will be manipulated using genetically engineered cell lines developed in aim 2 or by treating animals with bicarbonate or ammonium (to raise or lower pHe, respectively). Recent and exciting data indicate that this approach effectively increases the sensitivity of breast tumor xenografts to doxorubicin, a clinically common chemotherapeutic agent used to treat breast cancer. Further in vivo verification of this model may stimulate the development of chemotherapies that will more effectively account for the acid pHe of tumors.
Showing the most recent 10 out of 83 publications
