Demetrius Kokkinakis, Ph.D.
Associate Director of Pathology
E-mail: dmk8613@pitt.edu
Research Interests:
Most carcinogens and in many cases chemotheraputic agents exert their mutagenic and cytotoxic effects first by damaging DNA. There are several types of DNA damage which, if not repaired, cause variable cellular responses. These responses determine whether the cells exposed to genotoxic agents will survive without alterations in their
genetic make up, die, or mutate, in some cases to become malignant. Cell response depends on several factors including, but not limited to: 1) type of DNA damage, 2) capacity of the cell to repair the multiple types of DNA damage induced by most agents, 3) ability of the cell to retard its cycle thus allowing repair mechanisms to complete
the restoration of DNA before division, 4) ability of the cell to proof read newly synthesized DNA for abnormalities in order to maintain fidelity of DNA replication. A normal cell has more or less intact mechanisms to deal with various kinds of chemical or physical assaults. However, normal cells show various responses to DNA damage,
hence, the well known organotropy of carcinogens. More variable is the response of tumor cells to DNA damage since tumor cells, not only vary depending on which site and what cell tumors arose from, but also due to the high degree of cellular heterogeneity among the same tumor. Dr. Kokkinakis's laboratory has been involved in studies to understand the organotropy of carcinogens for more than 20 years. These studies have lead to the development of animal models for the study of pancreatic and CNS tumors which have resulted in the identification and study of target cell populations in these two organs. More recently the laboratory has been involved in studies to improve the cytotoxic effects of genotoxic chemotherapeutic drugs, based on modulation of DNA repair pathways, as part of combined modality approach chemotherapy. The following areas of study are active and funded by the National Cancer Institute:
- Development of an animal model for the study of progression of glial tumors: This project has so far resulted in the identification of the stem cells in the CNS (glial progenitor cells in particular) as being the targets of carcinogens to yield glial neoplasms. Cells at various stages of propagation (from normal to fully malignant) have
been isolated and are being studied in terms of their morphology, immunohistochemistry, growth factor dependence, motility, mortality and gene expression (studied by c-DNA microarray analysis). With this approach we expect to identify the progressive mutations leading to the fully malignant astrocytic and oligodendroglial tumor phenotype in the CNS.
- Understanding what makes glial tumors resistant to chemotherapy: The DNA repair pathways of several human glial tumors is studied in order to identify common weaknesses in the panoply of glial neoplasms to resist genotoxic damage. One of the most common features of resistance of astrocytic tumor cells is the bypassing of restrictions that prevent error prone DNA replication which are present in normal astrocytes. Astrocytic cancer cells can easily escape cell cycle blocks and proof reading repair systems that are designed to maintain fidelity during DNA replication.
- Designing chemotherapeutic regimens to treat glial tumors: Non-genotoxic stress has been shown to enhance the efficacy of DNA-damaging drugs in inducing apoptosis in astrocytic tumor cells. Drugs or regimens that induce stress either by inhibiting DNA repair and/or by extending cell cycle blocks during which DNA damage remains unrepaired, enhance the cytotoxicity of genotoxic drugs against glial tumors. Stress induced by methionine deprivation, as well oxidative stress, are tested in combination with traditional chemotherapeutic agents against glial neoplams using animal model systems.
Selected Publications:
Friedman HS, Kokkinakis DM, Pluda, J, et al. Phase 1 Trial of O6-Benzylguanine for Patients Undergoing Surgery for Malignant Gliomas; J. Clin. Oncol.,1998; 6:3570-3575.
Kokkinakis DM, Watson ML, Honig SH, Rushing EJ, Mickey BE, and Schold SC. Characterization of initiated cells in N-Methylnitrosourea induced
carcinogenesis of the central nervous system in the adult rat. Neuro-Oncology 2001, 2: 99-112.
Kokkinakis DM, Moschel RC, Pegg AE, Schold SC. Eradication of brain tumor xenografts with optional dosage combination of O6-benzyl-2'-deoxyguanosine and BCNU: Clinical Cancer Res. 5, 3676-3681.
Kokkinakis DM, Moschel RC, Pegg, AE, and Schold SC. Potentiation of BCNU anti-tumor efficacy by 9-substituted O6- benzylguanosines. Effect of metabolism. Cancer Chemother Pharmacol., 45, 69-77, 2000.
Kokkinakis DM, Hoffman, RM, Frenkel, EP, Wick JB, Han Q, Xu M, and Schold SC. Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice. Cancer Res., 61:4017-4023, 2001.
Kokkinakis DM, Bocangel DB, Schold SC, Moschel RC, and Pegg AE. Thresholds of O6-alkylguanine-DNA alkyltransferase which confer significant resistance of human glial tumor xenografts to treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea or temozolomide. Clin. Cancer Res 2001; 7: 421-428.
Kokkinakis DM, Zhou, XJ, and Wick, JB. Metabolic response of normal and malignant tissue to acute and chronic removal of methionine from the plasma of athymic mice bearing human glial tumor xenografts. Int. J. Cancer. In press
Bocangel D, Finkelstein S, Schold SC, Bhakat K, Mitra, S and Kokkinakis DM. Multifaceted Resistance of Gliomas to Temozolomide. Clin Cancer Res. In press.
