Leita A. Estes

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Illudins, novel natural products with a structure unrelated to any other known chemical, display potent in vitro and in vivo anti-cancer activity against even multi-drug resistant tumors, and are metabolically activated to an unstable intermediate that binds to DNA. The DNA damage produced by illudins, however, appears to differ from that of other known DNA(More)
Four second-generation Illudin analogues were synthesized and tested for antitumor activity using a metastatic lung carcinoma xenograft model resistant to conventional antitumor agents. One analogue, the parent illudofulvene-derivative called Acylfulvene, inhibited xenograft primary tumor growth and prolonged life span of tumor-bearing animals when(More)
The human lung carcinoma cell line MV522 was previously noted to produce extensive metastasis to the lungs, spleen and lymph nodes after subcutaneous transplantation into athymic nude mice. Animals eventually succumb to these metastases, and not primary tumor growth. The ability to produce extensive metastasis after a simple subcutaneous injection in 100%(More)
Acylfulvene, derived from the sesquiterpene illudin S by treatment with acid (reverse Prins reaction), is far less reactive to thiols than illudin S. However, it is reduced readily to an aromatic product, in the same way as illudin S. This may explain its greatly improved therapeutic index compared to that of the parent compound.
Reaction of the fungal sesquiterpene illudin S with excess paraformaldehyde in dilute H2SO4 gives (hydroxymethyl)acylfulvene. The primary allylic hydroxyl thus formed can undergo very facile replacement by a variety of nucleophiles. (Hydroxymethyl)acylfulvene (MGI.114) was more toxic than a precursor, acylfulvene, but less toxic than the parent compound(More)
Illudins are a novel class of agents with a chemical structure entirely different from current chemotherapeutic agents. A new semisynthetic derivative, MGI 114 (NSC 683,863, 6-hydroxymethyl-acylfulvene, HMAF), is markedly effective in a variety of lung, breast and colon carcinoma xenograft models. This analogue, MGI 114, is currently in phase I human(More)
This study is part of an effort to evaluate efficacy of the novel agent MGI 114 (HMAF) against tumors resistant to conventional chemotherapeutic agents. MGI 114 is a novel semisynthetic anticancer agent currently in chemotherapeutic phase II trials to evaluate activity against various solid tumors. Previous studies indicate MGI 114 was active against human(More)
The aim of this study was to determine theantitumor activity of irofulven whenadministered in combination with a varietyof antimitotic agents. Irofulven incombination with either paclitaxel ordocetaxel demonstrated synergistic activityin both the in vitro and invivo studies. The majority of xenograftbearing animals that received suboptimal (< MTD) doses of(More)
The structure and regulation of the microsomal glutathione S-transferase gene (MGST1) are considerably more complex than originally perceived to be. The MGST1 gene has two alternative first exons and is located in the 12p13.1-13.2 region. Two other potential first exons were determined to be nonfunctional. The region between the functional first exons(More)
Illudin analogs are cytotoxic to a variety of multidrug resistant cell lines, and display an unusual toxicity towards DNA helicase-deficient cell lines. Earlier illudin analogs demonstrated efficacy in several xenograft models, including a metastatic MV522 lung cancer model, resistant to conventional anticancer agents. These illudin analogs prolonged life(More)