Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors.

BACKGROUND: Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours. METHODS: Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m(-2) and CP 60-75 mg m(-2). Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m(-2), CP 60 mg m(-2)) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days. RESULTS: On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m(-2), 60 mg m(-2)); G 3 anorexia/fatigue/hypokalemia (1.2 mg m(-2), 60 mg m(-2)); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m(-2), 60 mg m(-2)). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m(-2), 60 mg m(-2)); G 4 mucositis (1.4 mg m(-2), 60 mg m(-2)); and G 3 hypokalemia (1.2 mg m(-2), 75 mg m(-2)). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m(-2) (days 1, 8) and CP 75 mg m(-2) (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers). CONCLUSIONS: On the 21-day cycle, eribulin mesylate 1.2 mg m(-2), administered on days 1 and 8, in combination with CP 75 mg m(-2), administered on day 1 is well tolerated and showed preliminary anticancer activity.

Anesthetic properties of some fluorinated oxolanes and oxetanes.

BACKGROUND: The search for new potent inhaled anesthetics has slowed, in large part because of the excellence of the two most recent additions, desflurane and sevoflurane. Nonetheless, neither desflurane nor sevoflurane are ideal anesthetics, desflurane causing cardiorespiratory stimulation, and sevoflurane having a slower (albeit rapid) recovery from anesthesia. Sevoflurane also can produce convulsions and postoperative agitation. METHODS AND RESULTS: In the present report, we describe the physical and anesthetic properties of 31 cyclic ethers halogenated solely with fluorine. Although several produced anesthesia, none had solubilities that would make them better than sevoflurane. The remaining ethers were unstable or produced obvious central nervous system irritation, including convulsions. CONCLUSIONS: We find that none of these cyclic ethers appear to provide advantages over desflurane or sevoflurane.

Caspase activation and death induced by yessotoxin in HeLa cells.

We have studied the death response induced by yessotoxin (YTX) in cultured HeLa cells, and have compared it to that triggered by okadaic acid (OA) in the same experimental system. Sub-nanomolar concentrations of YTX were found to induce HeLa cell death after a 48-96-h incubation. YTX caused loss of intact poly(ADP-ribose)-polymerase (PARP) in HeLa cells, and detection of the 85kDa fragment, which is indicative of proteolytic attack by caspases. Measurements of caspase activities using extracts prepared from YTX-treated cells and substrates of the caspase-3/7 and caspase-2 isoforms, showed that the relative proteolysis of caspase-3/7 substrate was about eight-fold higher than that of caspase-2, the levels of which were about twice those measured with extracts from control cells. These findings were matched by Western blot analyses of caspase-2, -3 and -7 in HeLa cell extracts, which showed that the levels of pro-caspase-2 were not greatly affected by YTX treatment, whereas pro-caspase-3 and -7 were activated in YTX-treated cells. Taken together, these data complement others previously obtained with OA, and support the notion that caspase isoforms involved in cell death induced by OA and YTX are cell- and toxin-specific.

Induction of morphological transformation in BALB/3T3 mouse embryo cells by okadaic acid.

Okadaic acid is produced by several types of dinoflagellates (marine plankton) and has been implicated as a causative agent of diarrhoetic shellfish poisoning. Okadaic acid, a known tumour promoter in vivo, has been shown to promote morphological transformation of carcinogen-initiated BALB/3T3 cells. This study shows that okadaic acid is capable of inducing morphological transformation of BALB/3T3 cells in the absence of an initiator.

Electron microscopy of tubuloreticular structures in allergic patch test. Observations with 2,3-epoxypropyl trimethyl ammonium chloride.

Tubuloreticular structures (TRS) are intracellular tubular inclusions that can be detected by means of electron microscopy. TRS have earlier been found in autoimmune, viral and neoplastic diseases. Here the occurrence of TRS is for the first time described in allergic patch tests, where they were detected in dermal macrophages. TRS are believed to be reaction products of metabolically active cells, and the TRS described here are probably formed as a result of the activation of the immune system in allergic patch tests.

Leukocytosis and low serum IgA in workers exposed to the epoxy compound, t-methyl-3-phenylglycidate.

Forty-nine out of 54 male workers engaged in the production of an epoxy compound, t-methyl-3-phenylglycidate, showed skin symptoms in varying degrees that may be due to the skin-irritative effect of the compound. The exposed workers were also shown to have subjective symptoms which may be related to the irritative property of the compound on surface tissue. Laboratory examinations on the blood obtained from the exposed workers showed significantly higher values of leukocyte concentration as compared with the non-exposed controls. This was chiefly caused by the increase of neutrophilic granulocytes and T-cell lymphocytes. Serum IgA levels of the exposed workers were shown to be significantly lower than those of the control group. Hemoglobin concentration, hematocrit value and red cell count of the exposed workers remained at the same level as those of the control subjects. Liver or kidney damage was not found in biochemical analyses on the sera of exposed workers.

Allergic contact dermatitis from a nonbisphenol A epoxy in a graphite fiber reinforced epoxy laminate.

An employee of the Composites Division of an aircraft engine manufacturing firm developed dermatitis associated with the handling of a graphite fiber reinforced epoxy laminate (epoxy prepreg). Patch test investigation demonstrated that the responsible causal agent was the nonbisphenol A epoxy binder, 4-glycidyloxy-N, N-diglycidylaniline. A patch test with bisphenol A epoxy from a standard patch test screening series was negative. Subsequent interviews with employees of the Composites Division suggested that a relative lack of awareness of the cutaneous hazards of fiber reinforced epoxy laminates, compared with liquid epoxy resin systems, may be an important risk factor for allergic sensitization to these composite materials.

Hair bulb accumulation of Langerhans cells in allergic patch tests.

The occurrence of occupational allergic contact dermatitis due to 2,3-epoxypropyl trimethyl ammonium chloride (EPTMAC) is reported and supplemented with immunohistochemical and electron microscopic observations. Four young workers developed hand dermatitis at a factory in which modified, cationic starch is manufactured. EPTMAC, a quaternary ammonium compound used as a cationizing chemical in the process, produced allergic reactions in all four patients in epicutaneous testing. The patients had only been in contact with EPTMAC for a short time (one to three months) before developing allergic eczema, which indicates that EPTMAC is a strong sensitizer. Immunohistochemistry showed that dendritic OKT6+ cells (Langerhans cells) increase in the hair follicles and the peribulbar infiltrate during the allergic patch test indicating that hair follicles might actively be involved in delayed type allergic reactions, possibly as a shunt way for allergens. Using electron microscopy, mitotic immunocompetent cells were found in the epidermis during the allergic patch test.

Allergic contact sensitization to the glycidyl ester of hexahydrophthalic acid in a cutting oil.

Allergic contact dermatitis is reported in 5 machine operatives working with a cutting oil containing an epoxy compound used as a stabilizer. Positive patch test reactions to this compound were obtained in all 5 men and were negative in 25 controls.

Occupational dermatitis to 2,3-epoxypropyl trimethyl ammonium chloride.

4 workers developed hand dermatitis in an automated starch modification process plant. 2,3-epoxypropyl trimethyl ammonium chloride (EPTMAC), a quaternary ammonium compound used as a cationizing chemical, produced allergic reactions in all 4 patients. They had only been in contact with EPTMAC for a short time before developing dermatitis, which indicates that EPTMAC is a strong sensitizer. Immunohistochemistry and electron microscopy showed the features of an allergic patch test. An industrial hygiene project was initiated at the factory to prevent new cases. It revealed many risks of skin contact with the process chemicals. Thus an automated process does not guarantee protection.

Unscheduled DNA synthesis correlated to alkylation of hemoglobin in individuals occupationally exposed to propylene oxide.

Exposure to propylene oxide was determined previously by the degree of alkylation of hemoglobin measured on the histidine residue as N-3-(2-hydroxypropyl) histidine, using blood samples from 8 propylene oxide-exposed employees and 13 unexposed referents. Mononuclear leukocytes isolated from the same blood samples were used to quantify DNA repair proficiency following an in vitro challenge with the carcinogen, N-acetoxy-2-acetylamino-fluorene. Decreases in the DNA repair proficiency index correlated significantly to in vivo exposure levels to propylene oxide (r = -0.64, p less than 0.03). These data suggest a possible short-term biological assay for monitoring the in vivo genotoxic effects of propylene oxide exposure in the human population.

Sister-chromatid exchanges and chromosome aberrations in lymphocytes from monkeys exposed to ethylene oxide and propylene oxide by inhalation.

The ability of long-term exposures to inhaled ethylene oxide (EO) and propylene oxide (PO) to induce sister-chromatid exchanges (SCEs) and chromosome aberrations in peripheral lymphocytes of monkeys was investigated. Five groups of adult male cynomolgus monkeys were exposed at 0 (shared control), 50, or 100 ppm EO, and at 100 or 300 ppm PO (7 hr/day, 5 days/week) for 2 years. EO exposures at 50 and 100 ppm resulted in statistically significant increases in sister-chromatid exchange rates and in the incidence of chromosome aberrations in monkey lymphocytes. Both EO-exposed groups had increased numbers of SCEs/metaphase compared to controls, with the SCEs/metaphase of the EO 100 ppm group also significantly elevated versus the EO 50 ppm group. Variability of SCEs/metaphase within each monkey increased even more than the increase in total SCEs/metaphase group with increasing EO exposure. Chromatid-type aberrations were also significantly increased for both EO 50 and EO 100 ppm groups compared to controls. Statistically significant increases in the number of chromosome-type aberrations (excluding gaps) were found only in the EO 100 ppm group. Combined chromatid- and chromosome-type aberrations were increased in both EO 50 and EO 100 ppm groups. No group differences in the number of gaps were found. In lymphocytes from monkeys exposed at 100 and 300 ppm PO, there were no group differences compared to controls for any variable-chromatid or chromosome-type aberrations, gaps, or SCEs/metaphase. These results indicate that EO is a more potent clastogen than PO and demonstrate, for the first time, statistically significant effects of EO on both SCEs and chromosome aberrations in lymphocytes of nonhuman primates.

Carcinogenic and toxicologic effects of inhaled ethylene oxide and propylene oxide in F344 rats.

The chronic inhalation toxicity and carcinogenicity of ethylene oxide (EO) and propylene oxide (PO) were evaluated in a 2-year inhalation bioassay. Five groups of male weanling Fischer 344 rats, 80 per group, were exposed at 0 ppm (shared control; filtered air), 50 ppm EO, 100 ppm EO, 100 ppm PO, or 300 ppm PO (7 hr/day, 5 days/week) for 104 weeks. Body weights from rats exposed to EO and PO at all exposure concentrations were significantly reduced compared to controls. A statistically significant increase in mortality was observed in all groups of exposed rats compared to controls. Skeletal muscle atrophy in the absence of any sciatic nerve neuropathology was found in rats exposed at 100 ppm EO and 300 ppm PO. Statistically significant associations between EO exposure and an increased incidence of the following rat neoplasms were observed: mononuclear cell leukemia, peritoneal mesothelioma, and mixed cell brain glioma. Among rats exposed to PO there was a dose-dependent increase in the incidence of complex epithelial hyperplasia in the nasal passages, and two adenomas were detected in the nasal passages of rats exposed at 300 ppm PO. The incidence of adrenal pheochromocytomas was elevated in both PO exposure groups, but not in a dose-related manner. All rat groups were affected by an outbreak of Mycoplasma pulmonis infection which occurred about 16 months into the study. This infection alone and in combination with the epoxide exposures affected the survival of rats in this study, and influenced the development of the proliferative lesions in the nasal mucosa of the PO-exposed rats. No treatment-related changes in any clinical chemistry or urinalysis indices were detected. PO exposure did not increase the incidence of the three neoplasms associated with EO exposure; however, adrenal pheochromocytomas and proliferative lesions of the nasal cavity were increased in rats exposed to PO.

Contact dermatitis from the epoxy resins tetraglycidyl-4,4'-methylene dianiline and o-diglycidyl phthalate in composite material.

An outbreak of dermatitis occurred in an aircraft factory using epoxy resin composite material. Of 25 operatives, 14 gave positive patch test reactions to the composite material and/or diglycidylether of bisphenol A (DGEBA), tetraglycidyl-4,4'-methylene dianiline (TGMDA), and o-diglycidyl phthalate. This report seems to be the first to demonstrate contact allergy to the two last mentioned epoxy resins. The diglycidylether of bisphenol A used in routine test series picked up only 3 cases of 12 tested.

Hydantoin-induced teratogenesis: are arene oxide intermediates really responsible?

A large body of literature indicates that prenatal exposure to hydantoin anticonvulsant drugs can be teratogenic and therefore result in offspring with congenital malformations [6, 10-12, 18, 27, 30]. Literature discussing the actual etiologic agent responsible for the malformation and the types of anomalies typical of hydantoin-induced teratogenicity is contradictory [3, 10, 11, 35]. The majority of published cases of the fetal hydantoin syndrome have been associated with maternal ingestion of the most widely prescribed of all the hydantoin anticonvulsants, phenytoin (Dilantin; Parke, Davis) [11]. Occasional reports of mephenytoin (Mesantoin; Sandoz) teratogenicity have been noted [10-11, 27], but our review of the literature yielded only one case report of birth defects in a child exposed to ethotoin (Peganone; Abbott Laboratories in utero [38]. We wish herein to describe three siblings prenatally exposed to ethotoin, all of whom had clinical features compatible with in utero exposure to hydantoin anticonvulsants. Unlike phenytoin and mephenytoin, ethotoin is not metabolized through an arene oxide intermediate. The presence of these clinical findings suggests, therefore, that epoxide metabolites are not the causative agents in hydantoin-induced teratogenicity.