Publishing ID: 1524
Sequencing Evaluation of MGI-114 Combinations with Standard Chemotherapy Agents Against
Human Tumor Cell Lines.
H. Barrera, Rodney Moore, S. J Waters, J. R MacDonald, S. Weitman, Institute for Drug Development, CTRC,
San Antonio, TX; MGI Pharma, Inc, Bloomington, MN.
6-Hydroxymethylacylfulvene (MGI-114), a semisynthetic antitumor agent derived from the mushroom toxin illudin S., was
evaluated in combination with SN-38, mitoxantrone, or gemcitabine against human colon, prostate, and pancreatic tumor cell
lines. These studies were undertaken to determine the drug-drug interaction (e.g., additive, synergistic, or antagonistic) that
exists between MGI-114 and standard agents and the importance of sequence of exposure to these agents. Multiple
combinations of MGI-114 with the standard cytotoxic agent were used with a model free design (Laska, et al. Biometrics
50:834, 1994) to describe the type of drug-drug interaction. These studies suggest that regardless of sequence of exposure
between MGI-114 and standard chemotherapy agents, an additive pattern of drug-drug interaction is most typically observed.
However, as previously observed, an occasional synergistic (concurrent exposure with mitoxantrone or SN-38; pre-exposure
to MGI-114 followed by SN-38) or additive/synergistic (pre-exposure to gemcitabine or SN-38) pattern of drug-drug
interaction was observed. Evidence of antagonism was observed only when the DU-145 prostate tumor cell line was
pre-exposed to MGI-114 or mitoxantrone. These studies suggest that MGI-114 which is in multiple Phase II clinical trials,
could be combined with several cytotoxic agents against a broad-range of tumor types. |
