Natasha Kyprianou

“Thymineless” death in androgen-independent prostatic cancer cells

The molecular mechanism of thymineless death induced by 5-fluorodeoxyuridine or trifluorothymidine, in androgen-independent rat prostatic adenocarcinoma AT-3 cells was investigated. Fragmentation of genomic DNA into discrete multiples of a nucleosomal unit (i.e. 180bp subunit) and induction of expression of TRPM-2, a programmed cell death-associated gene, temporally correlated with the activation of programmed cell death in this system. In contrast, killing of AT-3 cells by osmotic lysis, or membrane-targeted metabolic inhibitors results in neither the stereotypic DNA fragmentation into nucleosomal oligomers nor the elevation of TRPM-2 mRNA levels but to non-specific biochemical changes characteristic of necrosis. These results suggest that androgen-independent prostatic cancer cells retain a major portion of the programmed cell death cascade which can be activated by non-androgen ablative cytotoxic drugs that induce thymineless death.

Development of androgen-independent tumor cells and their implication for the treatment of prostatic cancer.

SummaryDevelopment of androgen-independent prostatic cancer cells from androgen-responsive cells can occur by a variety of mechanisms (e.g., environmental adaptation, multifocal origin, or genetic instability). Regardless of the mechanism of development, however, once androgen-independent cancer cells become present within prostatic cancer, the tumor is no longer homogeneous but is now heterogeneous. Once a prostatic cancer is heterogeneously composed of both androgen-dependent and-independent cancer cells, androgen withdrawal therapy, no matter how complete, cannot be curative. In order to produce cures of such heterogeneous prostatic cancers, hormonal therapy must be combined simultaneously with chemotherapy early in the course of the disease so that all the cancer populations (i.e., androgen-dependent and-independent) can be simultaneously affected within an individual patient.

Therapeutic Approaches to Activating Programmed Cell Death of Androgen-Independent Prostatic Cancer Cells

During this year there will be approximately 30 thousand deaths due to prostatic cancer in the United States (1). This mortality rate makes prostatic cancer the second commonest fatal tumor in males of all ages in America, and the leading cause of cancer death in men over the age of 55 (1). Besides a high annual mortality rate, prostatic cancer is now the most commonly diagnosed malignancy in males of all ages in the United States (1). These high annual incidence rates translate into the human reality that one of every 12 American white males will eventually develop clinical prostatic cancer during their lifetimes (2). Rates for American black males are even higher such that the lifetime risk for cancer is one out of every 10 (3). In addition, the annual incidence rate of clinical prostatic cancer has increased steadily since 1930 to the present time (4).