[Cancer chemo-endocrine therapy and its cell biological basis]

The aim of our cell kinetic studies is to better understand the effects of chemo-endocrine therapy at the cell biological and molecular level. Cancer cell growth is characterized by uncontrolled proliferation, resulting in DNA distribution pattern in which, at any time, more cells are not G1 phase but in S, G2 and M phase of a shortened cycle. In a recent progress, flow cytometry (FCM) has become a powerful tool for the quantitative analysis of cell cycle parameters by measuring nuclear DNA content in large cell population with high speed. With the aid of FCM in earlier work about 60-80% of ovarian cancers were found to contain aneuploid cells. Now, multi-parameter FCM linked to a computer is available to measure fluorescent intensities not only no base total DNA (Propidium iodide) but also A-T (Hoechst 33342) and G-C (Mithramycin) base pairs in solid cancer nuclei. Since cisplatinum (CDDP) is the most important drug in the treatment of ovarian cancer, we have studied the relationship of CDDP cytotoxicity, pertubations cell cycle kinetis and DNA damage in ovarian adenocarcinoma cells in vitro & in vivo. We employed both CDDP sensitive cell line (KFt) and resistant cell line (KFr) derived from human serous cystoadenocarcinoma of the ovary by Kikuchi et al (JNCI 1986). Comparing cell kinetic pertubations of experimental cells demonstrates a decrease in G1 phase cells concomitant increase in S phase cells. The KFr cells had distinctly a shorter S-phase block up to 24 hrs not A-T but G-C preference in a quick response followed repairing of DNA damage to 48 hrs. However, some fractions of CDDP resistant cell population showed a later onset of G2, M phase accumulation. Comparison with the increase in early S phase cells of KFr in detailed analysis suggests only those damaged cells that are not killed immediately may proceed to G1 phase and start into DNA synthesis in S phase. Measurement of labeling index (L. I.) with Bromodeoxyuridine (BrdU) support our interpretation of differences between sensitivity and resistance to anti-cancer drug. Additionally, we discuss a targeting chemotherapy by coupling cytotoxic drugs with estrogen based on increasing DNA damage into apoptosis and interfares with DNA repair process.