Phase I dose escalation of paclitaxel in patients with advanced ovarian cancer receiving cisplatin: rapid development of neurotoxicity is dose-limiting.

PURPOSE: To determine the maximum-tolerable dose (MTD) of paclitaxel in a phase I dose-escalation study when combined with cisplatin in patients with advanced ovarian cancer receiving filgrastim for prophylaxis of myelosuppression. PATIENTS AND METHODS: A total of 23 patients with stage II (bulky residual), III, or IV epithelial ovarian cancer were treated (following debulking surgery) with paclitaxel as a 3-hour infusion followed by cisplatin (75 mg/m2) administered over 4 hours on day 1, repeated every 21 days for six cycles. Filgrastim (5 micrograms/kg/d) was administered subcutaneously (SC) beginning on day 2 of each cycle through neutrophil recovery (absolute neutrophil count [ANC] > 10,000/microL). Patients were assigned to one of six escalating dose levels of paclitaxel: 150 (n = 3), 175 (n = 3), 200 (n = 3), 225 (n = 4), 250 (n = 4), and 275 mg/m2 (n = 6). RESULTS: At each paclitaxel dose level (150, 175, 200, 225, 250, and 275 mg/m2), the numbers of patients who completed six cycles without dose reduction were three (100%), three (100%), two (66%), two (50%), three (75%), and zero (0%), respectively. The numbers of patients who experienced a grade III/IV adverse event (hematologic or nonhematologic) were zero (0%), two (66%), two (66%), one (25%), four (100%), and five (80%), respectively. Reasons for dose reduction included neurotoxicity (225 mg/m2, n = 1; 275 mg/m2, n = 2), neutropenia (225 mg/m2, n = 2), diarrhea (275 mg/m2, n = 2), and nephrotoxicity (225 mg/m2, n = 1). Reasons for not completing six cycles at full or reduced dose included neuropathy (200, 225, and 275 mg/m2, n = 1 each) physician request (275 mg/m2, n = 1), and death (275 mg/m2, n = 1). Hematopoietic toxicity was minimal. Six patients developed grade III/IV neutropenia. No patient developed thrombocytopenia below a level of 50,000/microL. CONCLUSION: The MTD of paclitaxel was determined to be 225 mg/m2 when administered as a 3-hour infusion and combined with cisplatin (75 mg/m2). Nonhematologic dose-limiting toxicities were neuropathy and diarrhea. The neuropathy often had a rapid onset, especially at the higher dose levels.

Dendritic-NK cell interactions in P. gingivalis-specific responses.

Patients with localized aggressive periodontitis have type-1 cytokines in gingival crevicular fluid and high titers of IFN-gamma-dependent IgG2 reactive with P. gingivalis in gingival crevicular fluid and serum. Localized aggressive periodontitis monocytes spontaneously differentiate into dendritic cells that can stimulate IFN-gamma production by NK cells. These relationships prompted the hypothesis that P. gingivalis-dendritic cell-NK cell interactions might promote type-1 cytokine responses. Although P. gingivalis is not a potent inducer of Th1 responses, it stimulated strong IL-12 responses by monocyte-derived dendritic cells in the presence of IFN-gamma, and IFN-gamma was produced by NK cells within 24 hrs in the presence of dendritic cells. Anti-P. gingivalis IgG2 responses were enhanced by dendritic cells, and removal of NK cells reduced IFN-gamma- and P. gingivalis-specific IgG2. Thus, P. gingivalis-dendritic cell-NK cell interactions apparently resulted in reciprocal stimulation and increased type-1 cytokine production by both dendritic cells and NK cells, and increased P. gingivalis-specific IgG2.

Effects of neutralization of luteinizing hormone on corpus luteum function and cyclicity in Macaca fascicularis.

The primate corpus luteum (including the human) is thought to require continuous exposure to LH for normal progesterone production and menstrual cyclicity. Recently, normal luteal function was reported in rhesus monkeys after postovulatory hypophysectomy or treatment with an antagonist to GnRH. We studied the effects of neutralization of LH by specific antiserum in the fascicularis monkey. A potent antiserum to ovine LH, which cross-reacted with monkey pituitary extract, was produced in rabbits; this antiserum was administered daily to cycling monkeys during the midluteal phase. The pretreatment cycle duration was 32.4 +/- 1.7 (+/- SE) days, and luteal length was 16.5 +/- 0.8 days, with a midluteal progestin peak of 15.28 +/- 2.23 ng/ml. LH antiserum treatment resulted in a precipitous fall in serum progestin within 24 h, which remained low for the remainder of the cycle. All treated monkeys had premature menstrual bleeding, with mean cycle length shortened to 22.8 +/- 1.6 days (P less than 0.0005). These results confirm that the continuous presence of LH is essential for maintenance of corpus luteum function in this species of primate.

SK&F107647: a synthetic hematoregulatory peptide in patients with solid tumor malignancies: a phase I trial.

SK&F107647 is a synthetic hematoregulatory peptide (HP) increases both the number and function of progenitor cells, enabling improved survival after lethal myelosuppression, lethal fungal infection, and lethal herpes simplex virus infection in murine models. This Phase I single-blind placebo-controlled dose-rising crossover trial examined the efficacy of SK&F107647 in patients who had incurable solid tumor malignancies. Sixteen patients were treated. Six adverse events in 3 patients were considered to be possibly related to SK& F107647; all were mild to moderate in nature (mild nervousness and agitation at 0.01 ng/kg, moderate fever and mild nausea at 0.1 ng/kg, elevated hepatic enzymes at 0.1 ng/kg, and mild vomiting at 1.0 ng/kg). Plasma half-life was 2.44 hours (+/-1.07 standard deviation). The observed area volume of distribution was 16.7 L (+/-7.7 standard deviation) and clearance was 5.04 L/hour (+/-1.83 standard deviation). When administered as a single 2-hour intravenous infusion at doses ranging from 0.01 to 100 ng/kg, SK&F107647 is safe and well tolerated.

Absorption and biokinetics of U in rats following an oral administration of uranyl nitrate solution.

The absorption of U within the male Wistar rat was determined following oral gavage with uranyl nitrate solutions at seven different dosages. Gavage levels ranged from 0.003 to 45 mg U per kilogram body weight. Uranium tissue burdens were determined at 0.25, 0.5, 1, 2, 4, 8, 24, 48, 96 and 240 h following gavage. Blood, kidney, liver and bone were analyzed for U content using neutron activation followed by delayed neutron counting. Uranium rapidly localized in the kidneys and bone following ingestion. Bone was found to be the primary tissue of deposition. Skeletal and kidney burdens closely paralleled each other from 15 min to 10 d after oral gavage. Uranium burdens in the blood reached a maximum within 30 min but declined rapidly thereafter. Burdens of all tissues were well correlated with each other and with dosage at all dose levels. Equations relating body burdens with blood levels were developed and found to be useful for predicting body burdens for the initial 8 h following gavage. Gastrointestinal absorption (f1) was 0.6-2.8% over the range of U administered. Movement of U through the GI tract was assessed at two dosages. The transit time of U through the GI tract was approximately 48 h. Uranium loss from the stomach was described as a power function of time. The maximum value in the small intestine was attained within 2 h, and thereafter its rapid loss was linear up to 8 h. A minor residual loss component from the small intestine was evident beyond 8 h post-gavage.

Metabolism of ingested U and Ra.

The literature on metabolism of U and Ra for man relevant to deriving drinking water standards has been reviewed and summarized. Radium is well understood, but significant gaps remain in our knowledge about U metabolism. Limits should be based on an equilibrium model where a constant relationship between intake and organ burden is established, using the best and most likely metabolic parameters. For the skeleton we conclude that the best estimate of skeletal burden expressed in days equivalent intake are 25 days for 226Ra, 10 days for 228Ra, and 0.3 days for 224Ra. For long-lived isotopes of U, we chose 11 days, with a range between 1 and 35 days. The committee believes that intake of natural U in water should be limited by considerations of toxicity to the kidney, and we believe that the metabolic model of Spoor and Hursh with a modified gastrointestinal (GI) absorption (1.4%) should be used to infer kidney content. Our review and analysis of the world literature leads us to believe the average human GI absorption of U is most likely 1-2% and is probably reasonably independent of age or the mass of U ingested. Using a safety factor of 50-150, the committee recommends a limit of U in water of 100 micrograms/l in order to limit toxic effects in the kidney. One hundred micrograms/liter is equivalent to 67 pCi/l of long-lived alpha-emitting natural U isotopes. Further research into the distribution of U in the human body is desirable, especially at natural levels in kidney and skeleton, the time-dependent pharmacokinetics of U in animals, the GI absorption of U in man from water and food, toxicological and U distribution studies in animals under conditions of chronic oral U intake, and metabolic model error propagation.

Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis.

Caspases mediate apoptosis and have also been implicated in stem-cell biology. How caspases are linked to stem-cell biology is not known. Here, we show that the apoptotic blebs of cancer cells fuse together to form novel structures called 'blebbishields'. Blebbishields form spheres by fusion. Both blebbishield formation and sphere formation involve active caspases and N-linked glycosylation. Sphere formation is enhanced by acidic pH and is counteracted by inhibitors of proton pump, caspases, and cholesterol. The blebbishields from VEGFR2(High) cells are capable of enhanced sphere formation. Blebbishields express transiently downregulated stem-cell markers and the sphere-forming blebbishield-derived cells are tumorigenic. Our study demonstrates that the cancer stem cells can survive after apoptosis by blebbishield formation and subsequent sphere formation.

Role of motility in experimental cholera in adult rabbits.

The role of motility in the pathogenesis of cholera was evaluated in ligated ileal loops of adult rabbits. Four strains of Vibrio cholerae (including both Inaba and Ogawa serotypes of both classical and El Tor biotypes) were compared with their aflagellated, but fully toxigenic and prototrophic, isogenic derivatives as to their ability to produce fluid accumulation in the rabbit gut. The nonmotile mutants required an at least 100-fold-higher dose than their respective wild-type strains to produce comparable fluid accumulation responses. The decreased ability of nonmotile strains to produce a fluid response was not due to their failure to multiply in vivo, since they increased in numbers in the rabbit ileum at the same rate as the wild-type strains, but probably was related to their inability to associate with the intestinal mucosa. After 3 h of incubation, 45 to 53% of motile, [35S]-labeled cells adsorbed to the intestinal wall, whereas only 3 to 15% (depending upon the strain) of the nonmotile bacteria were associated.

Flagella-induced immunity against experimental cholera in adult rabbits.

The adult rabbit ligated ileal loop model was used to evaluate the prophylactic potential of a crude flagellar (CF) vaccine produced from the classical. Inaba strain CA401. A greater than 1,000-fold increase in the challenge inoculum was required to induce an intestinal fluid response in actively immunized adult rabbits equivalent to that produced in unimmunized animals. Similar protection was afforded against challenge with classical and El Tor biotypes of both Inaba and Ogawa serotypes. Highly virulent 35S-labeled vibrios were inhibited in their ability to associated with the intestinal mucosa of CF-immunized rabbits. The protection conferred by CF immunization was found to be superior to that of a commercial bivalent vaccine and also to that of glutaraldehyde-treated cholera toxoid. The critical immunogenic component of CF appears to be a flagella-derived protein. The immunogenicity of CF was destroyed by heat treatment, and absorption of CF-immune serum with aflagellated mutant vibrios did not diminish its ability to confer a high level of passive protection. The intestinal protection of CF-immunized rabbits was completely reversed by the introduction of both goat anti-rabbit immunoglobulins A and G, but by neither alone.

Nonpenetrating gunshot injury as a cause of testicular rupture.

We report 2 cases of testicular rupture owing to a nonpenetrating gunshot injury. Immediate surgical exploration on the basis of a large painful scrotum of acute onset accorded a correct diagnosis and appropriate treatment.