We examined paclitaxel for anti‐tumor activity against human lung cancer xenografts in nude mice and compared its efficacy with that of cisplatin, currently a key drug for lung cancer chemotherapy. Five non‐small cell lung cancers (A549, NCI‐H23, NCI‐H226, NCI‐H460 and NCI‐H522) and 2 small cell lung cancers (DMS114 and DMS273) were chosen for this study, since these cell lines have been well characterized as regards in vitro and in vivo drug sensitivity. These cells were exposed to graded concentrations of paclitaxel (0.1 to 1000 nM) for 48 h. The 50% growth‐inhibitory concentrations (GI50) for the cell lines ranged from 4 to 24 nM, which are much lower than the achievable peak plasma concentration of paclitaxel. In the in vivo study, 4 cell lines (A549, NCI‐H23, NCI‐H460, DMS‐273) were grown as subcutaneous tumor xenografts in nude mice. Paclitaxel was given intravenously as consecutive daily injections for 5 days at the doses of 24 and 12 mg/kg/day. Against every xenograft, paclitaxel produced a statistically significant tumor growth inhibition compared to the saline control. Paclitaxel at 24 mg/kg/day was more effective than cisplatin at 3 mg/kg/day with the same dosing schedule as above, although the toxicity of paclitaxel was similar to or rather lower than that of cisplatin, in terms of body weight loss. In addition, paclitaxel showed potent activity against 2 other lung cancer xenografts (NCI‐H226 and DMS114). Therefore, paclitaxel showed more effective, wider‐spectrum anti‐tumor activity than cisplatin in this panel of 6 lung cancer xenografts. These findings support the potential utility of paclitaxel in the treatment of human lung cancer
The morphology, chemotaxonomy, and cultural and physiological characteristics were examined on the five strains of actinomycetes which produce antiviral antibiotics, fluvirucin congeners. All strains have raes0-2,6-diaminopimelic acid in the cell wall. Four strains, Q464-31, L407-5, R359-5 and R5 16-16, belong to the maduromycetes since they have madurose in the whole cell. The remaining one strain, R869-90, has rhamnose but no madurose, and is a nocardioform actinomycete. These five strains were classified and designated as follows: In the course of searching for new antiviral antibiotics from the fermentation broth of soil microorganisms, five unusual actinomycetes were found to produce a family of antibiotics consisted of seven components, designated fluvirucins Al9 A2, Bl9 B2, B3, B4 and B5. The production, biological and chemical properties and structure of fluvirucins were described in the preceding papers1~3). This paper describes the characterization and taxonomic position of these five unusual actinomycete strains. Materials and MethodsThe cultural and physiological characteristics of the five strains were examined by the methods of Shirling and Gottlieb40, and Gordon et al.5). Diagnostic components of amino acid and sugar in the whole cell hydrolysate were analyzed by the methods of Lechevalier6). The phospholipids were identified by the methods of Lechevalier et al.n). The menaquinone samples were prepared by the procedures of Collins et al.8) and analyzed with a mass spectrometer. The glycolate test and the detection of mycolate were carried out by the methods ofUchida and Aida9), and Minnikin et al. l0), respectively. The composition of methyl esterified cellular fatty acids was analyzed by GC with SPB-1 fused silica capillary column (0.25 mmx 30m), and determined by GC-MS. ResultsThe morphology, cell chemistry, fatty acid composition, and cultural and physiological characteristics Preclinical Research Laboratories, 1 Futagoyama, Sakazaki, Kohda-cho, Nukata-gun, Aichi Prefecture 600, Japan.
Paclitaxel, an antineoplastic agent, was administered intravenously to pregnant Crj: CD (SD) rats daily at dose levels of 0 (saline and vehicle), 0.1, 0.3 and 1.0 mg/kg from day 17 of gestation to postpartum day 21. Results were as follows: 1. The vehicle-treated group had no effect in any of the parameters that were measured in this study when compared to the saline-treated group. 2. 1.0 mg/kg paclitaxel caused suppression of the body weight gains associated with the decreased food consumption in F0 dams during the lactation period. 3. Thymic, heart and uterine weights were reduced in 1.0 mg/kg F0 dams at completion of the lactation period. In addition, thymic atrophy was observed for 1.0 mg/kg F0 dams macroscopically. 4. Paclitaxel did not alter the delivery status of F0 dams or birth, viability and weaning indices in F1 pups. 5. The days required for presence of hair, incisor eruption and testicular descent were statistically delayed in 1.0 mg/kg F1 rats. 6. The latency time for olfactory orientation was prolonged in 1.0 mg/kg F1 rats on postnatal day 15. Further, the positive response rates for air righting were reduced in 1.0 mg/kg F1 rats from postnatal day 17 to day 20. 7. 1.0 mg/kg paclitaxel caused suppression of the body weight gains in male F1 rats from postnatal week 1 to week 12. Though body weight gains were decreased in 1.0 mg/kg female F1 rats from postnatal week 1 to week 7, there were no significant differences between dosed animals and saline-treated animals regarding the body weight gains and food consumption during the gestation period. 8. Paclitaxel did not affect the learning ability and memory, spontaneous motor activity or emotionality in F1 rats. 9. The reproductive performance in both male and female F1 rats were not affected by paclitaxel. 10. Splenic weights were reduced in 1.0 mg/kg male and female F1 rats at weaning. Furthermore, liver weights were decreased in 1.0 mg/kg male F1 rats after mating. 11. No influence on prenatal development was observed for F2 fetuses even at the highest dose level of paclitaxel. Based on the reproductive and developmental indices, the no toxic-effect dose level of paclitaxel is 1.0 mg/kg/day and 0.3 mg/kg/day for dams (F0) and their offspring (F1), respectively.
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