Richard,
The abstracts are now online. You can access them after registering at the following link:
aacr98.expocity.com
A search for MGI-114 produced four abstracts, reproduced below (I assume quoting 4 abstracts out of umpteen is considered fair use <g>):
[PROC. AMER. ASSOC. CANCER RES. 39, March 1998]
Copyright c 1998 by the American Association for Cancer Research
#3588 In vitro antitumor activity of MGI 114 in combination with topotecan, taxol, cisplatin, etoposide, or gemcitabine against pediatric tumor cell lines. H. Barrera, J. MacDonald, S. Hilsenbeck, S. Weitman. University of Texas Health Science Center, San Antonio, TX 78284, MGI Pharma, Minnetonka, MN 55343.
6-Hydroxymethylacylfulvene (MGI 114) is a novel semisynthetic antitumor agent derived from the mushroom toxin illudin S. These studies were designed to generate isoeffect plots following exposure to MGI 114 in combination with other antitumor drugs using neuroblastoma, rhabdomyosarcoma, medulloblastoma, and Ewing's sarcoma cell lines. Cells were exposed to various concentrations of MGI 114 and study drug for 1 hour, followed 5 days later by the MTT assay. Statistically significant antitumor synergy was observed with MGI 114 and topotecan in 10/12 (83%) cell lines. Synergy was most pronounced in neuroblastoma and rhabdomyosarcoma cell lines. Evidence of synergy was found in 2/4 (50%), 4/15 (26%), 1/5 (20%), and 1/6 (17%) cell lines for combinations of MGI 114 with cisplatin, etoposide, taxol, and gemcitabine, respectively. These studies suggest that the combination of MGI 114 with topotecan, or other topoisomerase I inhibitors, should be considered for in vivo evaluation.
#3585 Evidence of synergistic antitumor activity with MGI 114 in combination with Irinotecan (ITN) or 5-Fluorouracil (5-FU) against a human colon tumor xenograft model. J. Marty, J. MacDonald, G. Mangold, S. Weitman, D. Von Hoff. Institute for Drug Development, San Antonio, TX 78245, MGI Pharma, Minnetonka, MN 55343.
6-Hydroxymethylacylfulvene (MGI 114) is a novel semisynthetic antitumor agent derived from the mushroom toxin illudin S. MGI 114 (3.5 and 7 mg/kg;qdx5;i.p.) was administered alone and in combination with ITN (50 and 100 mg/kg; days 1, 12, 19;i.p.) or 5-FU (50 and 100 mg/kg;days 1, 12, 19;i.p.) to mice bearing the HT-29 human colon xenograft. At 3.5 mg/kg, MGI 114 produced tumor growth inhibition (TGI) of 69.5%. At 7 mg/kg, TGI was 92.3% (2/9 animals) and mean tumor shrinkage was 60.5% (7/9 animals). TGI, but no tumor shrinkage was observed with ITN or 5-FU alone. When MGI 114 (3.5 mg/kg) was combined with ITN, there were 3 complete responses. The remaining animals (7/9, ITN-50; 8/9, ITN-100) had mean tumor shrinkage of > 75%. When MGI 114 (3.5 mg/kg) was combined with 5-FU there were 5/9 (5-FU-100) animals with mean tumor shrinkage of 58% and no complete responses. These studies suggest that the combination of MGI 114 with either ITN or 5-FU produces synergistic antitumor activity compared to single agent responses.
#1553 Efficacy of MGI 114 in the myeloid leukemia HL60/MRI xenograft model. Kelner, M.J., McMorris, T.C., Estes, L.A., and MacDonald, J.R. University of California, San Diego, 92093, MGI PHARMA, Minneapolis, MN 55343.
Illudins are novel toxic natural products isolated from the Jack O' Lantern mushroom (Omphalotus illudens). MGI 114 (HMAF; NSC 683863) is a semisynthetic illudin analog, with favorable in vitro and in vivo activity that is currently in phase I human trials, and scheduled for phase II human trials against a variety of solid tumors. Illudin S was previously noted to have marked in vitro activity against myeloid, but not B- or T-cell derived leukemia cells. Therefore, the anti-leukemic activity of MGI 114, and several other illudin-derived analogs, was determined using the HL60/MRI myeloid leukemia xenograft. MGI 114 was found to markedly inhibit tumor growth (P < 0.001) in the HL60/MRI model, at 7 mg/kg (daily x 5, i.p.) and 10 mg/kg (3X/week, i.p.) for 3 weeks, with tumor growth inhibition significantly greater than that of other illudin analogs and several conventional antitumor agents. These results suggest that the activity of MGI 114 against myeloid derived leukemias should be evaluated in phase II clinical trials.
#453 Uptake and macromolecular binding of 6-hydroxymethylacylfulvene (HMAF, MGI 114) in a leukemic cell line, CEM. Herzig, M.C.S., Arnett, B., MacDonald, J.R., and Woynarowski, J.M. Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, TX 78245, MGI Pharma, Minnetonka, MN 55343 (JRM).
6-Hydroxymethylacylfulvene (HMAF, MGI114) is a novel antitumor drug and a potent pro-apoptotic agent that has the potential to alkylate cellular nucleophiles. The objective of these studies was to characterize drug uptake and to examine cellular targets for drug binding using [14C]-HMAF. Drug uptake of 10æM [14C]-HMAF at 37øC in the sensitive human leukemia cell line CEM had two components: a rapid uptake from 0-10 min of 0.72 pmol/min/106cells and a slower non-saturating rate of 0.11pmol/min/106cells. HMAF uptake was dependent on temperature with low temperature (4øC) inhibiting uptake by 82% at 4 hr. After a 4 hr drug treatment at 37øC with 5 æM [14C]-HMAF, CEM cells had accumulated up to 43 pmol [14C]-HMAF/106 cells. Perchloric acid precipitation revealed that approximately 31 pmol was covalently bound to macromolecules. Combinations of DNase, RNase and Proteinase K with perchloric acid precipitation showed that 57%, 28% and 15% of the bound radiolabel co-precipitated with the protein, DNA, and RNA fractions, respectively. Nearly 76% of the radiolabel was retained by the cells with a similar macromolecular-adduct distribution 20 hr after drug treatment. In contrast to drug binding to cellular DNA, no [14C]-HMAF binding to naked SV40 DNA at a 1:1 molar ratio of drug to base pair of DNA was detected. These results show that a majority of the cell-associated HMAF binds covalently to macromolecules. HMAF binding to non-DNA targets and HMAF bio-activation prior to DNA binding may contribute to the action of the drug. (Sponsored by MGI Pharma). |
