Illudins are low molecular weight natural products which were previously evaluated as anticancer drugs using rodent
tumor models. In the present studies, we used in vitro cultures of human
cancer cells to reevaluate their potential as
anticancer agents. Using continuous exposure, Illudins S and M were cytotoxic to human
leukemia cells at concentrations of 6-100 nM, but
dihydroilludin M was 3 orders of magnitude less toxic, thus identifying a
ketone site as a structural feature critical for cytotoxicity. Cytokinetic studies showed that
illudin S caused a complete block at the G1-S phase interface of the cell cycle. Kinetics of inhibition of radiolabeled
thymidine,
uridine, and
leucine incorporation suggested a primary effect on
DNA synthesis. In colony and liquid culture assays, cell killing was time dependent but near maximal with a 2-h exposure. Myeloid and T-lymphocyte
leukemia cells were most sensitive (50% inhibitory concentration, 6-11 nM), but
B-cell leukemia/
lymphoma,
melanoma, and ovarian
carcinoma cells were at least 10 times more resistant. Bone marrow granulocyte/macrophage progenitors showed intermediate sensitivity.
Illudin S was equally effective against CEM T-lymphocyte
leukemia cells expressing the multidrug resistance phenotype associated with Mr 180,000
glycoprotein and the parental cell line. CEM cells resistant to
doxorubicin, epipodophyllotoxins, and 1-beta-D-arabinofuranosylcytosine showed only a 2-fold increased resistance to
illudin S. Illudins are novel and potent
cytotoxins which may be preferentially active against human myeloid and
T-cell leukemias, including cells resistant to more conventional chemotherapeutic agents. The present studies illustrate the breadth of information which can be obtained on a new agent using present in vitro screening procedures and human cells.