A series of chalcones was evaluated as antimitotic agents. One of these, (E)-1-(2,5-dimethoxyphenyl)-3-[4-(dimethylamino)phenyl]-2-methyl-2-pr open- 1-one) (73), was found to be an effective antimitotic agent at a concentration of 4 nM in an in vitro HeLa cell test system. When evaluated in experimental tumor models in vivo, this compound exhibited antitumor activity against L1210 leukemia and B16 melanoma.

Cytoplasmic extracts of HeLa cells synchronized in various phases of the cell cycle were injected into fully grown Xenopus laevis oocytes to monitor the presence of factors that can induce meiotic maturation: i.e., germinal vesicle breakdown and chromosome condensation. Extracts from GI and S phase cells had no activity. The maturation-inducing activity, which was found to be low during early and mid G2 phases, increased rapidly during late G2 and reached a peak in mitosis. The results of this study suggest that the factors that regulate the breakdown of nuclear membrane and chromosome condensation during mitosis, meiosis, and premature chromosome condensation appear to be very similar, if not identical, throughout the anima kingdom. The fusion between a mitotic and an interphase cell usually leads to the breakdown of the interphase nucleus and the condensation of chromatin into discrete chromosomes under the influence of the factors present in the mitotic cell. This phenomenon, which resembles the initiation of mitosis, has been termed premature chromosome condensation (PCC) (1). Mitotic cells of human origin (HeLa), upon fusion, can induce PCC in cells from a variety of animal species including mammals, birds, amphibians, fishes, and insects, and mitotic cells from these species can induce PCC in HeLa cells (2). The mitotic factors have been found to migrate to the interphase nucleus and subsequently become associated with the prematurely condensed chromosomes (3). In order to isolate and characterize the mitotic factors, it is essential to have an in vitro system in which PCC can be induced without resorting to cell fusion. Until now, however, we were unable to induce PCC in either whole cells or isolated nuclei by incubating them with mitotic extracts under a variety of conditions.In our search for a suitable model, we found the amphibian oocytes desirable. In amphibians, meiotic maturation of ovarian oocytes involves breakdown of the nuclear envelope (germinal vesicle), chromosome condensation, and progression through the first meiotic division. This maturation process can be induced by incubating fully grown oocytes with progesterone in vitro (4-6). Meiotic maturation can also be induced in amphibian oocytes by injecting them with cytoplasmic extracts from maturing oocytes (7-9). Recent reports indicate that maturation-promoting activity is present not only in maturing oocytes but also in early cleavage stages of amphibian embryos, which undergo cell division with a high degree of synchrony (10). The activity of cytoplasmic extracts appears to fluctuate during the division cycle of the embryonic nuclei and reaches a peak during mitosis (10). Further, it was shown that introduction of somatic cell nuclei into maturing oocytes leads toThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. MATERIALS AND METHODSCells and Cell Synchrony. HeLa cells were grown as monolayer cultures at 37...

Purpose: Oral mucositis is a common acute morbidity associated with radiation and/or chemotherapy treatment for cancer. D-Methionine (D-Met), the dextro-isomer of the common amino acid L-methionine, has been documented to protect normal tissues from a diverse array of oxidative insults. Experimental Design: We evaluated if D-Met could selectively prevent radiation-induced oral mucositis using in vitro cell culture models as well as an in vivo model of radiation injury to the oral mucosa in C3H mice. Results: Unlike free-radical scavengers, which protected both normal and transformed tumor cells in vitro from radiation-induced cell death, treatment with D-Met in culture protected nontransformed primary human cells from radiation-induced cell death (protective factor between 1.2 and 1.6; P < 0.05) whereas it did not confer a similar protection on transformed tumor cells. D-Met treatment also provided significant protection to normal human fibroblasts, but not to tumor cell lines, from radiation-induced loss of clonogenicity (protection factor,1.6 F 0.15). D-Met treatment did not alter DNA damage (as measured by histone phosphorylation) following irradiation but seemed to selectively mitigate the loss of mitochondrial membrane potential in nontransformed cells, whereas it did not provide a similar protection to tumor cells.Tumor control of implanted xenografts treated with radiation or concurrent cisplatin and radiation was not altered by D-Met treatment. Pharmacokinetics following administration of a liquid suspension of D-Met in rats showed 68% bioavailability relative to i.v. administration. Finally, in a murine modelof mucositis, a dose-dependent increase inprotection was observed with the protective factor increasing from 1.6 to 2.6 over a range of oral D-Met doses between 200 and 500 mg/kg (P < 0.0003).Conclusions: D-Met protected normal tissues, but not tumor cells, in culture from radiationinduced cell death; it also protected normal cells from radiation-induced mucosal injury in a murine model but did not alter tumor response to therapy. Further studies on the use of D-Met to protect from oral mucositis are warranted.

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