Preclinical evaluation of illudins as anticancer agents.
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.
Kelner
M J
MJ
McMorris
T C
TC
Beck
W T
WT
Zamora
J M
JM
Taetle
R
R
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division; D002460:Cell Line; D004247:DNA / Q000032:analysis; D004351:Drug Resistance; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D008970:Molecular Weight; D010641:Phenotype; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D006023:Glycoproteins; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; C052673:illudin M; C052674:dihydroilludin M; D004247:DNA; C008105:illudin S