The prognostic impact of serum testosterone during androgen-deprivation therapy in patients with metastatic prostate cancer and the SRD5A2 polymorphism.

BACKGROUND: Although testosterone suppression during androgen-deprivation therapy (ADT) and obesity have been reported to affect ADT efficacy, there are few comprehensive analyses on the impact on ADT outcome. Recently, we demonstrated that the SRD5A2 polymorphism was associated with metastatic prostate cancer prognosis. Therefore, in this study, we investigated the relationship between ADT serum testosterone levels or body mass index (BMI) and the prognosis among men treated with primary ADT for metastatic prostate cancer. In addition, we examined the association of serum testosterone levels during ADT with the SRD5A2 polymorphism. METHODS: This study included 96 Japanese patients with metastatic prostate cancer. The relationship between clinicopathological parameters, including serum testosterone levels during ADT and BMI, and progression-free survival, overall survival and survival from progression following primary ADT treatment for metastatic prostate cancer was examined. Additionally, the association between the SRD5A2 gene polymorphism (rs523349) and serum testosterone levels during ADT was examined in 86 cases. RESULTS: Among clinicopathological parameters, the lowest quartile of serum testosterone levels during ADT was a significant predictor of better overall survival as well as survival from castration resistance. However, BMI was not associated with prognosis. The CC allele in the SRD5A2 gene (rs523349), encoding the less active 5α-reductase, was associated with lower serum testosterone levels during ADT. CONCLUSIONS: Taken together, these findings revealed a dramatic suppression of serum testosterone by ADT was associated with better survival among men with metastatic prostate cancer that have undergone primary ADT, which may be affected by the SRD5A2 gene polymorphism.

Oxidative stress and DNA hypermethylation status in renal cell carcinoma arising in patients on dialysis.

Renal cell carcinoma (RCC) is more frequently observed in patients on dialysis than in patients with normal renal function. However, the mechanism underlying carcinogenesis in RCC patients on dialysis is still unclear. We hypothesized that oxidative stress affects patients on dialysis and generates new neoplasms, and therefore analysed the correlation between the influences of various markers of oxidative stress and carcinogenesis in those patients. We evaluated the immunohistochemical expression of oxidative stress markers, such as iNOS, 8-OHdG, and COX-2 in 42 cases on dialysis and 51 cases with normal renal function as a control. The methylation status of p16INK4a, p14ARF, VHL, and RASSF1A was analysed together with clinicopathological factors. Histologically, the papillary type was observed more frequently in dialysis RCC than in sporadic RCC. Immunohistochemically, overexpression of iNOS (p < 0.0001) and COX-2 (p = 0.0002) was more frequently observed in dialysis RCC. Furthermore, the 8-OHdG labelling index was significantly higher in dialysis RCC than in sporadic RCC. Hypermethylation of p16INK4a was more frequently found in dialysis RCC (p < 0.05). However, no significant correlations between oxidative stress markers and DNA hypermethylation status were observed. The overexpression of iNOS, COX-2, and 8-OHdG in dialysis RCC suggests that patients on dialysis are affected by oxidative stress and that this effect plays an important role in the genesis of dialysis RCC.

Structure-activity relationship studies on 4''-O-acyltylosin derivatives: significance of their 23-O-mycinosyl and 4''-O-acyl moieties in antimicrobial activity against macrolide-resistant microbes.

Essential roles for both the 23-O-mycinosyl and 4''-O-acyl moieties of 4''-O-acyltylosin derivatives in the expression of antimicrobial activity against multiple macrolide-resistant strains of Staphylococci and mycoplasmas were demonstrated by in vitro comparison of the MICs of erythromycin, josamycin, tylosin and its 3- and 4''-O-acyl derivatives, demycinosyltylosin (DMT) and its 3- and 4''-O-acyl derivatives and 23-modified 3-O-acetyl-4''-O-isovaleryl-DMT derivatives.

Application of dibutyltin oxide method to regioselective acylation and alkylation of tylosin at C-4''.

4''-O-Acyl-, 4''-O-alkyl- and 4''-deoxy-tylosin derivatives were synthesized using 2'-O-acetyl-3'',4''-O-(dibutyl-stannio)tylosin as a synthetic intermediate. The in vitro biological evaluation showed that the new derivatives were active against macrolide-resistant clinical isolates of bacteria and mycoplasmas, and that they were resistant to hepatic esterase.

Synthesis and structure-activity studies of new 4''-O-acyltylosin derivatives of therapeutic interest.

Eleven 4''-O-acyltylosin derivatives were synthesized and subjected to a two-step screening system consisting of antimicrobial activity and esterase stability assays. The new derivatives were all active against macrolide-resistant Staphylococci and mycoplasmas, but only 4''-O-(4-methoxy)phenylacetyltylosin and 4''-O-(4-acetyl)phenylacetyltylosin showed better resistance to mouse liver esterase than 4''-O-phenylacetyltylosin (reference compound C).

New tylosin analogs produced by mutants of Streptomyces fradiae.

2'''-Demethoxytylosin (component IIIc), 2'''-demethoxy-4'''-epi-tylosin (component IIId) and 2'''-O-demethyltylosin (component Vb) were produced by blocked mutant strains of Streptomyces fradiae. Fermentation, isolation, structure determination and biosynthetic considerations of these tylosin analogs are described.

Studies of tylosin derivatives effective against macrolide-resistant strains: synthesis and structure-activity relationships.

The 4"-O-substituted tylosin derivatives were prepared by selective esterification of the 4"-OH, and relationships between the substituent groups and antimicrobial activity against macrolide-resistant strains were examined. Introduction of branched-chain aliphatic acyl groups such as 2-methoxyisovaleryl or 4-methylvaleryl group afforded derivatives with good antibacterial activity; MIC values were 12.5 microgram/ml against Staphylococcus aureus MS-8710. MIC values of tylosin, erythromycin and josamycin against this strain were 800 microgram/ml or more. Further improved activity was obtained by introduction of aromatic groups such as phenylthioacetyl, phenylsulfonylacetyl, 4-nitrophenylacetyl, 4-nitrophenylsulfonyl and phenylethanesulfonyl groups; MIC values were 6.25 microgram/ml. These derivatives had also an improved antimycoplasmal activity; MIC values were 0.08 microgram/ml against macrolide-resistant strains of Mycoplasma gallisepticum. MIC values of tylosin against these strains were from 2.5 to 10 microgram/ml. Introduction of the groups described above into the 4"-OH was confirmed to increase the uptake by a resistant strain.

New anthracyclines, feudomycins, produced by the mutant from Streptomyces coeruleorubidus ME130-A4.

Various blocked mutants were isolated from Streptomyces coeruleorubidus ME130-A4 by NTG and UV treatments. Among them, mutant strain 4N-140 produced new anthracycline feudomycins A and B having new aglycones in which the side chain at C-9 position of daunomycinone was ethyl and acetonyl, respectively. New aglycones feudomycinones C and D having methyl at C-9 and additional groups at C-10 of daunomycinone were also isolated from this strain.

Physico-chemical properties of new acyl derivatives of tylosin produced by microbial transformation.

By microbial transformation of tylosin (I), the following eight new acyl derivatives were obtained: 3-acetyltylosin (II), 3-propionyltylosin (III), 4"-butyryltylosin (IV), 4"-isovaleryltylosin (V), 3-acetyl-4"-butyryltylosin (VI), 3-acetyl-4"-isovaleryltylosin (VII), 3-propionyl-4"-butyryltylosin (VIII) and 3-propionyl-4"-isovaleryltylosin (IX).

Biological properties of new acyl derivatives of tylosin.

The antibacterial activity of acyl derivatives of tylosin were examined in vitro and in vivo. The 4"-acyl group in the acylated tylosins enhanced the antibacterial activity and antimycoplasmal activity against some macrolide-resistant strains. The orally administered 3-acetyl-4" -isovaleryltylosin produced a higher blood level in mice and rabbits than tylosin and a good therapeutic effect on the infection of Staphylococcus aureus Smith in mice.

PS-6 and PS-7, new beta-lactam antibiotics. Isolation, physicochemical properties and structures.

Antibiotics PS-6 and PS-7 which are shown to be 5R,6R-3-(2-acetamido)ethylthio-6-isopropyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene- 2-carboxylic acid and 5R,6R-3-(E)-(2-acetamido) vinylthio-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid respectively, are new beta-lactam compounds isolated from fermentation broths of Streptomyces cremeus subsp. auratilis A271, S. fulvoviridis A933, S. olivaceus ATCC 31126 and S. flavogriseus NRRL 8139. Fermentation, isolation, physicochemical properties and structures of antibiotics PS-6 and PS-7 are described.

Periodically repeated multi-phasic health tests--a unique data source for detecting subject-specific normal ranges.

When a comprehensive health check-up is repeated for the purpose of health control, the individual clinical data should be evaluated carefully by a proper normal range, which must be specific to each subject, if early detection of disease is a goal. The Perfect Liberty Health Control System, a health plan run on a membership basis, has been giving its periodic multi-phasic health tests to all of the 24 000 + members biannually since 1970. Studies concerning health parameter dynamics have been made on the data obtained and these are important to the new challenging field of clinical laboratory examinations. Other helpful aspects of this punctually repeated AMHTS (Automated Multi-phasic Health Testing) on a lifetime membership basis are also presented, such as cancer detection accuracy, protection from unnecessary X-ray exposure during examinations and a new form of physician's examination supported by current laboratory-data preview.