Substituted titanocenes induce caspase-dependent apoptosis in human epidermoid carcinoma cells in vitro and exhibit antitumour activity in vivo.

Titanocene compounds are a novel series of agents that exhibit cytotoxic effects in a variety of human cancer cells in vitro and in vivo. In this study, the antiproliferative activity of two titanocenes (Titanocenes X and Y) was evaluated in human epidermoid cancer cells in vitro. Titanocenes X and Y induce apoptotic cell death in epidermoid cancer cells, with IC50 values that are comparable to cisplatin. Characterisation of the cell death pathway induced by titanocene compounds in A431 cells revealed that apoptosis is preceded by cell cycle arrest and the inhibition of cell proliferation. The induction of apoptosis is dependent on the activation of caspase-3 and -7 but not caspase-8. Furthermore, the antitumour activity of Titanocene Y was tested in an A431 xenograft model of epidermoid cancer. Results indicate that Titanocene Y significantly reduced the growth of A431 xenografts with an antitumour effect similar to cisplatin. These results suggest that titanocenes represent a novel series of promising antitumour agents.

The Escherichia coli K-12 gntP gene allows E. coli F-18 to occupy a distinct nutritional niche in the streptomycin-treated mouse large intestine.

Escherichia coli F-18 is a human fecal isolate that makes type 1 fimbriae, encoded by the fim gene cluster, and is an excellent colonizer of the streptomycin-treated mouse intestine. E. coli F-18 fimA::tet, lacking type 1 fimbriae, was constructed by bacteriophage P1 transduction of the fim region of the E. coli K-12 strain ORN151, containing the tetracycline resistance gene from Tn10 inserted in the fimA gene, into E. coli F-18. E. coli F-18 fimA::tet was found to occupy a distinct niche in the streptomycin-treated mouse intestine when fed in small numbers (10(4) CFU) to mice, along with large numbers (10(10) CFU) of E. coli F-18, as defined by the ability of the E. coli F-18 fimA::tet strain to grow and colonize only 1 order of magnitude below E. coli F-18. The same effect was observed when mice already colonized with E. coli F-18 were fed small numbers of E. coli F-18 fimA::tet. Experiments which show that the E. coli K-12 gene responsible for this effect is not fim::tet but gntP, which maps immediately downstream of the fim gene cluster, are presented. gntP encodes a high-affinity gluconate permease, suggesting that the distinct niche in the mouse large intestine is defined by the presence of gluconate. The data presented here support the idea that small numbers of an ingested microorganism can colonize the intestine as long as it can utilize an available nutrient better than any of the other resident species can.

Escherichia coli F-18 and E. coli K-12 eda mutants do not colonize the streptomycin-treated mouse large intestine.

The Escherichia coli human fecal isolates F-18 and K-12 are excellent colonizers of the streptomycin-treated mouse intestine. E. coli F-18 and E. coli K-12 eda mutants (unable to utilize glucuronate, galacturonate, and gluconate) were constructed by insertional mutagenesis. Neither the E. coli F-18 eda nor the E. coli K-12 eda mutant was able to colonize the streptomycin-treated mouse intestine, whether they were fed to mice together with their respective parental strains or alone. Complementation of the eda mutants with pTC190 (containing a functional E. coli K-12 eda gene) completely restored the colonization ability of both eda mutants. Relative to their parental strains, the E. coli F-18 eda mutant and the E. coli K-12 eda mutant grew poorly in cecal mucus isolated from mice fed either normal mouse chow or a synthetic diet containing sucrose as the sole carbon source, yet the mutants and parental strains demonstrated identical growth rates in minimal medium with glucose as the carbon source. E. coli F-18 edd eda and E. coli K-12 edd eda double mutants colonized the streptomycin-treated intestine when fed to mice alone; however, when fed simultaneously with their respective parental strains, they were poor colonizers. Since the edd gene is involved only in gluconate metabolism via the Entner-Doudoroff pathway, these results implicate the utilization of gluconate and the Entner-Doudoroff pathway as important elements in E. coli colonization of the streptomycin-treated mouse large intestine.

Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics.

BACKGROUND: Development of tolerance to opioid analgesics occurs often in patients with cancer-related pain. Cross-tolerance among opioid analgesics provides the physician with a major management problem. Incomplete cross-tolerance among opioid analgesics has been demonstrated to occur in animals and humans. The current study provides clinical evidence of the incomplete cross-tolerance of methadone with a number of mu-opioid agonist analgesics in patients with advanced cancer-related pain. RESULTS: Patients presented in the current study had cancer-related pain refractory to other mu--opioid receptor agonist analgesics as evidenced by inadequate analgesia despite escalation of opioid dose. All patients were adequately managed by conversion of their opioid dose to methadone. Additionally, the dose of methadone required to establish and maintain analgesia in these patients was modest compared with previous opioid dose requirements. CONCLUSIONS: Methadone is a potent opioid analgesic that demonstrates incomplete cross-tolerance with other mu-opioid receptor agonist analgesics. Conversion of the opioid-tolerant patient with cancer-related pain to methadone may represent an important therapeutic option in the management of patients with this difficult problem.

Effect of position on the spread of buffered 2% chloroprocaine administered epidurally for the second stage of labor.

Increasing the pH of epidurally administered local anesthetics hastens their onset of action and improves the quality of neural blockade. The effect of body position on the epidural spread of alkalinized 2% chloroprocaine HCl for the second stage of labor has not been reported. We studied the epidural cephalad and caudad spread of 2% chloroprocaine buffered with sodium bicarbonate administered epidurally at the beginning of the second stage of labor. We randomly assigned 30 patients to one of two groups, each consisting of 15 patients. Group 1 received an epidural redose in the upright position, and the patients in group 2 received a redose in the supine position. There were no differences with respect to the sacral or cephalad spread. From the results of this study, we conclude that patients may receive epidurally administered 2% chloroprocaine late during the first stage of labor while in a supine position.

Alkalinization of chloroprocaine for epidural anesthesia: effects of pCO2 at constant pH.

Increasing the pH of 2% chloroprocaine (CP) with sodium bicarbonate to pH 7.7 hastens the onset of epidural analgesia. The purpose of the present study was to determine the effect of pCO2 on the onset of epidural analgesia with CP buffered to a constant pH 7.7. Four groups consisting of ten patients each were studied: C, control, commercial CP (pH 4.35); B, CP buffered with sodium bicarbonate (pH 7.7); T, CP buffered with tromethamine (pH 7.7), and BT, CP buffered with sodium bicarbonate and tromethamine (pH 7.7). All epidural catheters were placed at the L2-3 or L3-4 interspace using a loss-of-resistance technique with air with each patient in a sitting position. The pH and pCO2 of each local anesthetic solution were measured as well as the onset and duration of analgesia. The study groups did not differ with respect to demography or entry characteristics. There were intergroup differences in the pCO2 values of the study solutions as follows: Group 1 (C), 11.8 +/- 1.5 mmHg; 2 (B), 113.0 +/- 1.4 mmHg; 3 (T), 3.0 +/- 0.3 mmHg, and 4 (BT), 74.1 +/- 1.0 mmHg, respectively. The time to the onset of analgesia was significantly faster in Group 2 (B; 2.7 +/- 0.8 minute), while the onset of analgesia was significantly slower for Group 3 (T; 5.4 +/- 0.4 minute) than either Group 1 (C; 4.2 +/- 0.8 minute) or Group 4 (BT; 3.4 +/- 0.3 minute). Regression analysis revealed that the onset times of the buffered solutions were significantly related to pCO2 (r2 = 0.81).(ABSTRACT TRUNCATED AT 250 WORDS)