Application of the Microculture Kinetic (MiCK) Assay for Apoptosis to Testing Drug Sensitivity of Ovarian, Fallopian and Primary Peritoneal Adenocarcinomas

Trial Information

Application of the Microculture Kinetic (MiCK) Assay for Apoptosis to Testing Drug Sensitivity of Ovarian, Fallopian and Primary Peritoneal Adenocarcinomas

1. 0 Background and Rationale: Despite the use of aggressive treatment protocols, less
than 10% of cancer patients with an advanced disease respond to the therapy. There is a
variety of different cancer drug regimens, all of which have approximately the same
probability of clinical effectiveness. Identification of those patients who will or
will not respond to a specific chemotherapy is important for making decisions regarding
chemotherapy regimens as well as alternative management approaches. A laboratory test
that could help to determine the sensitivity of an individual patient's tumor cells to
specific chemotherapeutic agents would be valuable in choosing the optimal chemotherapy
regimen for that patient with an expectation of increasing the response rate to the
therapy. Several types of in vitro assays that measure tumor cell survival following
exposure to cytotoxic agents have been evaluated for their ability to predict
chemotherapy outcomes. As a group, these assays are referred to as drug resistance
assays. In a resistance assay, the surviving tumor cells can be detected directly by
their exclusion or metabolism of specific dyes. Alternatively, since some of tumor
cells are proliferating, their survival can be detected by measurement of DNA synthesis
by radiolabeled precursor incorporation or demonstration of clonogenic potential by
growth into colonies in semi-solid culture medium. In several clinical studies, these
assays were useful in detecting drug resistance and in predicting a poor prognosis for
cancer patients. However, these resistance assays cannot detect sensitivity of an
individual patient's tumor cells to a specific drug. Therefore, new methods
determining drug-sensitivity of the tumor cells of an individual patient and, thus,
capable of both predicting a positive treatment outcome and guiding chemotherapy, would
be of significant value.

Recently, Dr. Kravtsov has developed an automated microculture kinetic (MiCK) assay for
measuring drug induced apoptosis in tumor cells. Apoptosis is a distinct mode of cell death
which occurs under physiological conditions and yet can be induced in malignant cells by
chemical and physical factors including antitumor drugs. During the last decade, it has
been recognized that chemotherapeutic agents exert their antitumor activity by triggering
apoptosis in susceptible tumor cells. This implies that the MiCK assay for apoptosis
provides a mechanism-based approach to studying effects of cytotoxic agents on tumor cells.
Unlike "resistance" assays that measure a fraction of cells surviving drug exposure, the
MiCK assay measures a fraction of tumor cells killed by a chemotherapeutic agent via
mechanism of apoptosis. Therefore the MiCK assay determines drug sensitivity, rather than
resistance. Recently the MiCK assay has been shown to predict complete remission rate and
survival in acute myeloid leukemia patients better than clinical criteria did. In a limited
study, the MiCK assay has been used to direct chemotherapy of the leukemia patients .

The MiCK assay has also been used to study drug-induced apoptosis in solid tumors, including
neuroblastoma and colon adenocarcinoma cell lines. More recent data accumulated by DiaTech
has demonstrated that the MiCK assay can detect drug induced apoptosis in primary cultures
of tumor cells isolated from patients with ovarian carcinoma, gastric carcinoma, metastatic
breast cancer and high grade soft tissue sarcoma. Based on these data, we suggest that the
MiCK assay may be used to detect drug sensitivity profiles of individual patients with
various types of solid tumors. This, in turn, may provide a way to tailor chemotherapy to an
individual patient's drug sensitivity profile, and, thus, improve treatment outcomes,
decrease adverse effects of the chemotherapy, increase the quality of patient's life, and
reduce the treatment cost.