PhD, Yale University
Mechanism of Action of Cancer Chemotherapeutic Agents
Our research is directed towards obtaining a better understanding of the mechanism of action of cancer chemotherapeutic agents, which will lead to the more efficient use of existing agents and the design of new and more effective agents for the treatment of cancer.
In particular, we are interested in drugs that may have efficacy, in combination with ionizing radiation, in the treatment of solid tumours. Assuming that radioresistant hypoxic cells are a limitation to the curability of some human tumours, we are investigating drugs that can act as radiation sensitizers (oxygen mimics) and/or can be bioreductively activated resulting in enhanced toxicity towards hypoxic compared to aerobic cells. Three structurally different classes of drugs with selective toxicity towards hypoxic cells have been identified. They are 2-nitroimidazoles, mitomycins and benzotriazine dioxides. These drugs are selectively activated in the absence of oxygen to reactive intermediates which can damage DNA. We are actively pursuing the chemical identification of the reactive intermediates and determining their stability and molecular sites of reaction at a cellular and murine solid tumour level.
In the case of 2-nitroimidazoles, several reactive reductive intermediates, the nitroso and hydroxylamine, have been isolated and their interaction with DNA and cellular thiols is being assessed at the molecular level. This has led to a realization that the target for cell killing by these agents may have a cellular redox component as well as a direct DNA damage component and result in apoptotic cell death. New nitroimidazole derivatives have been synthesized which are attached to DNA intercalating moieties to see to what degree targeting this class of bioreductives to DNA affects their efficacy as radiosensitizers and hypoxic cell toxins.
One of the major variables controlling the sensitivity of cells to mitomycins is their profile of reductive enzymes such as DT-diaphorase and cytochrome P-450 reductase. Cells with differing enzyme levels have been isolated and transfection of specific reductase genes into appropriate cells is being utilized to gain information on the specific role these enzymes play in drug activation. It is becoming clear that cellular enzyme profiles involved in the metabolisms of xenobiotics is an important factor not only for mechanism of action of chemotherapeutic drugs, but also in a broader context of the carcinogenic potential of chemicals in the environment.
We are determining the oxygen dependency of bioreductive activation of nitroimidazoles and are studying technetium-99m labelled drugs as selective markers for hypoxic cells. These drugs are being tested for their potential to quantitate and image hypoxic cells in experimental solid tumours. If successful, these compounds may be used clinically to non-invasively detect and monitor hypoxic cells in solid tumours when exposed to radiation or chemotherapeutic drugs.
This overall approach has led us to a rational choice for drug-radiation combinations and for drug design based on consideration of both the genetic and microenvironmental factors that can influence the sensitivity of tumour cells to treatment.