Thomas P. Fondy, Professor of Biology
1. Evaluation of cytoskeletal-directed anti-neoplastic agents, rapamycin, and cholesterol-altering agents in combination with Low-frequency Ultrasound against neoplastic and normal cells in cell culture and in mouse models of cancer.
2. Treatment-induced cell-enlargement and multinucleation of neoplastic human cell lines in culture, as a potential approach to the selective physical destruction of neoplastic cells based on cell size, nucelar and DNA-content, and cytoskeletal and membrane structure.
3. Pulsed Low-Frequency Ultra-sound in the Preferential Physical Destruction of Neoplastic Cells in the presence of normal blood cells in Cell Culture and in Pre-clinical Animal Models
4. Cytochalasins as micro-filament-directed anti-neoplastic agents.
5. Application of Zebrafish as a non-mammalian vertebrate live animal model evaluation of approaches to the selective physical destruction of leukemia cells by whole-body treatment.
OnLine Course Web-sites;
Essay on Cancer Chemotherapy:
"In the Elevator at the Princess Margaret Hospital";
There Is Not More of Wonder:
Trafford Press, 2014
Degree: Ph.D, Duquesne University, 1961
Postdoctoral: Brandeis University, 1962-1965
Laboratory Research Interests: The Cytochalasins are a family of related molecules produced by molds that exert profound and remarkable effects on animal cells and tissues. These extensive effects arise from the ability of Cytochalasins to disrupt the microfilament cytoskeleton. The cytoskeleton is vital to cell and tissue functions such as plasma membrane constriction and cutting during cell division, regulation of entry into and passage through cell division, motility, secretion, wound healing, angiogenesis (formation of blood supply), and integrity of linings of the blood vasculature and intestines. These profound effects suggest that, in analogy with other cytoskeleton-directed agents such as Vinca-Alkaloids and Taxol which produce their effects by interaction with the micro-tubules of the cytoskeleton, the micro-filament directed Cytochalasins might have value as pharmacologically active agents in cancer chemotherapy. We have established such in vivo activity with cytochalasin B against mouse cancers including a leukemia, a melanoma, a lung carcinoma, and a sarcoma.
The activity of cytochalasins upon which we are focussing our efforts in the pre-clinical treatment of human, mouse, and fish cancers relates to the fact that cytochalasins induce cancer cells in culture to become heavily multinucleated because cytochalasins prevent membrane division but cannot stop nuclear replication. Normal cells when exposed to cytochalasins in culture will stop cytokinesis (membrane division) but they will also stop entering into the cell cycle to initiate nuclear replication and thus do not become multinucleated. Because damage to nuclei induced by DNA-reactive anti-cancer agents or by X-ray is known to induce apoptosis (intra-cellularly controlled cell-suicide), we propose that damage to one or more of the nuclei in a multinucleated cancer cell will initiate apoptosis in that cell even if some of the other nuclei are undamaged. Since the cancer cells are multinucleated, we propose that they have a greater chance of incurring DNA-damage to one or more of their nuclei than does a resting or even a dividing mononucleated normal cell.
Neoplastic cells often express a high degree of cell enlargement based on high growth fraction and often rapid passage through the cell cycle. A leukemic blast cell population has an modal cell size of 16 to 18u compared to normal red blood cells of 4 to 6u. The volume differential thus is 50-fold or more. Leukemia cells treated with anti-neoplastic agents, especially cytoskeletal-directed agents, become even more grossly enlarged. We propose that these cell size anomalies can be exploited in leukemia cell management by proprietary physical approaches that we are developing involving pulsed low-frequency ultra-sound. Moreover these anomalies may also be exploitable against carcinoma and sarcoma cell neoplasms that grow attached but must detach to divide, and against metastatic cells that exist as single cells or small cell emboli while in the metastatic state.
Research Articles: 2014-2015
1. Trendowski M, Christen TD, Andonova AA, Narampanawe B, Thibaud A, Kusang T, Fondy TP. Effects of mTOR inhibitors and cytoskeletal-directed agents alone and in combination against normal and neoplastic hematopoietic cells in vitro. Invest New Drugs 2015; 33(6): 1162-1174. (MS4A) Impact Factor: 2.92
2. Trendowski M, Christen TD, Acquafondata C, Fondy TP. Effects of cytochalasin congeners, microtubule-directed agents, and doxorubicin alone or in combination against human ovarian carcinoma cell lines in vitro. BMC Cancer 2015; 15(1): 632. (MS19) Impact Factor: 3.36
3. Trendowski M, Zoino JN, Christen TD, Acquafondata C, Fondy TP. Preparation, in vivo administration, dose-limiting toxicities, and antineoplastic activity of cytochalasin B. Transl Oncol 2015; 8(4): 308-317. (MS20) Impact Factor: 2.88
4. Trendowski M, Christen TD; Zoino JN; Fondy TP. Effects of alkylation and immunopotentiation against ehrlich ascites murine carcinoma in vivo using novel tetra-O-acetate haloacetamido carbohydrate analogs. Eur J Med Chem 2015; 98: 149-159. (MS22) Impact Factor: 3.45
5. Trendowski M, Christen TD, Zoino JN, Acquafondata C, Fondy TP. Generation and Quantitative Analysis of Pulsed Low Frequency Ultrasound to Determine the Sonic Sensitivity of Untreated and Treated Neoplastic Cells. J Vis Exp 2015; 101: e53060. (MS18A) Impact Factor: 1.33
6. Trendowski M, Wong V, Zoino JN, Gadeberg L, Sansky M, Fondy TP. Preferential enlargement of leukemia cells using cytoskeletal-directed agents and cell cycle growth control parameters to induce sensitivity to low frequency ultrasound. Cancer Lett 2015; 360(2): 160-170. (MS5) Impact Factor: 5.62
7. Trendowski M, Mitchell JM, Corsette CM, Acquafondata C, Fondy TP. Chemotherapy with cytochalasin congeners in vitro and in vivo against murine models.Edit This .(MS15A) Impact Factor: 2.92
8. Trendowski M, Mitchell JM, Corsette CM, Acquafondata C, Fondy TP. Chemotherapy in vivo against murine M109 lung carcinoma with cytochalasin B by localized, systemic, and liposomal administration. Invest New Drugs 2015; 33(2): 280-289. (MS15B) Impact Factor: 2.92
9. Trendowski M, Wong V, Yu G, Fondy TP. Enlargement and multinucleation of U937 leukemia and MCF7 breast carcinoma cells by antineoplastic agents to enhance sensitivity to low requency ultrasound and to DNA-directed anticancer agents. Anticancer Res 2015; 35(1): 65-76. (MS2) Impact Factor: 1.83
10. Trendowski M, Wong V, Wellington K, Hatfield S, Fondy TP. Tolerated doses in zebrafish of cytochalasins and jasplakinolide for comparison with tolerated doses in mice in the evaluation of pre-clinical activity of microfilament-directed agents in tumor model systems in vivo. In Vivo 2014; 28(6):1021-1031. (MS11A) Impact Factor: 0.97
11. Trendowski M, Yu G, Wong V, Acquafondata C, Christen T, Fondy TP. The real deal: Using cytochalasin B in sonodynamic therapy to preferentially damage leukemia cells. Anticancer Res 2014; 34(5): 2195-2202. (MS1) Impact Factor: 1.83
Patterns of Resistance to Cytochalasins in Drug Sensitive and Multidrug Resistant Human Ovarian Carcinoma and Murine Leukemia Lines. Thomas P. Fondy. General Motors Cancer Research Foundation International Symposium, Toronto, Canada, 1993
Cytochalasin B -Induced Immunosuppression of Murine Allogeneic Anti-Tumor Response and the Effect of Recombinant Human Interleukin-2. Dennis Bogyo, Susan R.E. Fondy, Luanne Finster, Christopher Fondy, Sheila Patil, and Thomas P. Fondy. Cancer Immunology and Immunotherapy, 32: 400-405 (1991).