Contradictory antitumor efficacies produced by the combination of DNA attacking drugs and polyamine antimetabolites

The antitumor effects of two polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG), when combined with cis-diamminedichlroplatinum (CDDP) or mitomycin C (MMC), were studied using human gastric cancer cells xenotransplanted into nude mice. DFMO 1000 mg/kg and MGBG 50 mg/kg were given intraperitoneally for 6 successive days, while CDDP 3 mg/kg or MMC 2 mg/kg was given every second day. Although DFMO and MGBG plus MMC did suppress the tumor growth, the combination with CDDP led to no suppression, and rapid growth occurred after the cessation of therapy. The inhibition of tumoral DNA biosynthesis and a decline in polyamine levels, were also not observed. The polyamine antimetabolites when used with CDDP did not produce the desired antitumor efficacy, even though the platinum concentration in the tumor tissue was high. On the contrary, however, DFMO and MGBG when combined with MMC did suppress tumor growth, inhibited DNA biosynthesis, and tissue polyamine levels were low. These results suggest that though CDDP and MMC belong to a similar category of DNA attacking, bifunctional alkylating agents, the findings of these two drugs are contradictory. Here, the mechanism of action no doubt plays a contributory role.     

Immunohistochemical and ultrastructural study on effect of fibroblast growth factor on transformation of fibroblasts to regenerated mesothelial cells

To elucidate the effect of fibroblast growth factor on the phenotypical conversion of fibroblasts to mesothelial cells, both immunohistochemical and ultrastructural examinations were carried out on cultured spheroids that were composed of fibroblasts obtained from the parietal pleura of rats with and without addition of antifibroblast growth factor receptor antibody. In the present study, antifibroblast growth factor receptor antibody was employed to block the effect of the autocrine component of fibroblast growth factor in the culture medium. Phenotypical conversion from fibroblast to mesothelial cells was clearly blocked in the experimental group, to which culture medium had been added with antifibroblast growth factor receptor antibody, whereas the control group, cultured without addition of antifibroblast growth factor receptor antibody, showed phenotypical conversion of fibroblasts that was confirmed by the development of macula adherens, microvilli, and positive expression of cytokeratin. These results indicate the possibility that fibroblast growth factor plays a key role in the process of phenotypic conversion of fibroblasts to regenerated mesothelial cells.     

Clinical results of intraperitoneal hyperthermic perfusion combined with surgery in patients with peritoneal recurrence from gastric cancer

Six patients with peritoneal recurrence after radical operation for gastric cancer were treated by an intraperitoneal hyperthermic perfusion (IPHP) combined with surgery (IPHP group). Immediately after surgery, a 2-hour IPHP was performed, using a perfusate containing 10 micrograms/ml of MMC, warmed at the inflow temperature of 46.5 +/- 1.1 degree C. Within the same period of time, 5 patients with intra-abdominal recurrent gastric cancer (control group) were treated by an intraperitoneal administration of MMC 10 mg combined with surgery. These 11 patients had malignant peritoneal effusion and, although in 3 of the control group, ascitic effusion did re-accumulate rapidly soon after surgery, the 6 patients of IPHP group did not re-accumulate post-hyperthermically. The average survival duration of IPHP group is 13.6 +/- 10. 6 months, whereas that for controls is 3.0 +/- 2.1 months. Again, the survival rate for IPHP group surpassed that for controls at p = 0.012 and p = 0.008, in a generalized Wilcoxon method and Logrank method, respectively. Post-hyperthermically, hypoproteinemia and thrombocytopenia occurred transitorily. These results show that IPHP using MMC combined with surgery is a safe, reliable treatment for patients with peritoneal recurrence due to gastric cancer.     

Disposition and excretion of Irgasan® DP300 and its chlorinated derivatives in mice

The distributions of radioactivity were examined by whole body autoradiography and liquid scintillation spectrophotometry in male ddY mice following oral administration of tritium-labelled Irgasan^® DP300 (2,4,4-trichloro-2-hydroxydiphenyl ether) (I) and its three chlorinated derivatives; 2,3,4,4-tetrachloro-2-hydroxydiphenyl ether (II), 2,4,4,5-tetrachloro-2-hydroxydiphenyl ether (III) and 2,3,4,4,5-pentachloro-2-hydroxydiphenyl ether (IV). The autoradiograms at 6 or 24 hr showed that the radioactivity distributed in the gall, liver, lung, heart, and kidneys. Among these tissues the radioactivity was most concentrated in the gall, suggesting the enterohepatic circulation of these compounds. A much higher level of radioactivity in each tissue was observed in mice receiving [³H]-III than the other compounds tested. Most of the radioactivity disappeared from each tissue in 24 hr due to [³H]-Irgasan DP300, [³H]-II or [³H]-IV, but in 96 hr it was due to [³H]-III.The cumulative radioactivity excreted in urine after administration of these compounds was in the order of [³H]-Irgasan DP300, [³H]-II, [³H]-IV and [³H]-III while that in feces was in the order of [³H]-IV, [³H]-III, [³H]-II and [³H]-Irgasan DP300,This work was presented at the 106th Annual Meeting of the Pharmaceutical Society of Japan (1986).     

Grading score system: A method for evaluation of the degree of senescence in Senescence Accelerated Mouse (SAM)

For evaluation of the degree of senescence in SAM-P, accelerated senescence prone mouse, formerly called SAM or prone series or P-series, consisting of SAM-P/1, SAM-P/2, SAM-P/3 and SAM-P/4 corresponding to P-1, P-2, P-3 and P-4 series, respectively, in the previous reports, and in SAM-R, accelerated senescence resistant mouse, formerly called resistant series or R-series, consisting of SAM-R/1, SAM-R/2 and SAM-R/3 corresponding to R-1, R-2 and R-3 series, respectively, in the previous reports, the grading score system was adopted. The items to be examined in this system include 11 categories selected from the clinical signs and gross lesions considered to be associated with the aging process. The degree of the senescence in each category was graded from 0 to 4 according to the detailed criteria devised in our laboratory. After 8 months of age each mouse was examined every 4 months, and some of the mice were examined after 2 months of age.In almost all categories, the grading score and incidence began to increase from 4 or 6 months of age and continued to increase with advancing age in both SAM-P and SAM-R. The increase, however, was more marked in SAM-P than in SAM-R. The slow but steady increase in the SAM-R levelled out at 24 months of age and was comparable to that of 12 months of age in SAM-P. In both SAM-P/1 at 8 months of age and SAM-R/2 at 12 months of age, there was a significant reverse correlation between total score of this grading score system and length of residual life after examination.Systematic and extensive studies using the grading score system showed that if the validity of the system is, based on “irreversibility” and “universality” of the changes in     

Association and crystallization of poly(ethylene oxide)

The discontinuous change of the lamellar thickness with crystallization temperature was studied for low molecular weight fractions of OH-terminated poly(ethylene oxide) (PEO). IR analyses demonstrated that almost all of the molecular chain ends were associated in the molten state, whereas a large part of their ends were free in dilute solution. Discontinuous changes were observed for low molecular weight PEO fractions crystallized from the melt, whereas continuous changes were found both for PEO's crystallized from dilute solution and those with phenylated end groups crystallized from the melt. Accordingly, it was pointed out that the association of the end groups could play an important role in the crystallization mechanism and the conformation of the resultant PEO crystals.     

Efficacy and immunologic responses to influenza vaccine in HIV-1-infected patients

Influenza vaccine is recommended for HIV-1-infected patients. The present prospective study was conducted to evaluate the clinical efficacy and immunologic responses to the vaccine. From November 1 to December 27, 2002, 262 HIV-1-infected patients received a trivalent influenza subunit vaccine, whereas 66 did not. Influenza illness occurred in 16 vaccinated and 14 nonvaccinated patients (incidence = 6.1% [95% confidence interval (CI): 4%-10%] in vaccinated vs. 21.2% [CI: 13%-35%] in nonvaccinated persons, P < 0.001; relative risk = 0.29 [CI: 0.14-0.55]). Influenza vaccine provided clinically effective protection against influenza illness in HIV-1-infected patients. In baseline antibody-negative patients, anti-H1 and anti-H3 antibody responses to the vaccination were significant in those patients with a CD4 count >200 cells/muL compared with those with a CD4 count <200 cells/muL (P < 0.05). In contrast, in baseline antibody-positive patients, good antibody responses were observed irrespective of CD4 counts, like the healthy controls. Based on these results, annual vaccination is recommended. Specific CD4 responses correlated with HIV-1 viral load (VL), especially in patients treated with highly active antiretroviral therapy (HAART) compared with those without HAART (P < 0.01), although the clinical efficacy did not correlate with HIV-1 VL. HAART may enhance the immunologic efficacy of influenza vaccine.     

Correlation between mutated genes and forearm deformity in patients with multiple osteochondroma

BackgroundsExostosin-1 (EXT1) and exostosin-2 (EXT2) cause multiple osteochondromas (MO). In this study, we investigated the correlation between forearm deformity and mutant EXTs in Japanese families with MO.MethodsWe evaluated 112 patients in 71 families with MO. Genomic DNA was isolated from peripheral blood leucocytes. Of these, 28 patients were selected and underwent radiography for their forearms since they had gross forearm deformities. We measured the radial articular angle (RAA), ulna variance (UV), carpal slip (CS), and percentage of radial bowing (%RB) to compare between patients with mutant EXT1 or EXT2 and those with missense or other mutations using Student's t-test.ResultsTwenty-two (78.6%) and 6 (11.4%) out of 28 patients had mutations in EXT1 and EXT2, respectively. Nine (32.1%) and 19 (67.9%) of the 28 patients had missense and other mutations, respectively. The mean age of patients with EXT1 and EXT2 were 25.9 ± 20.3 and 33.5 ± 25.4 years, respectively and those with missense mutation and other mutations were 28.7 ± 27.0 and 24.6 ± 17.0 years, respectively. There were no significant differences in RAA, UV, and RB between patients harbouring mutant EXT1 or EXT2 (RAA, 40.1 ± 8.7 and 31.5 ± 13.9°; UV, ?2.7 ± 5.7 and ?3.1 ± 3.7 mm; %RB, 8.6 ± 1.5 and 8.3 ± 2.0%). CS was significantly greater in patients with mutant EXT1 than that in those with mutant EXT2 (EXT1, 44.1 ± 16.8%; EXT2, 18.6 ± 14.0%). There were no significant differences in RAA, UV, CS and %RB between patients with missense and other mutations.ConclusionsPatients with mutant EXT1 displayed greater CS than patients with mutant EXT2, indicating that patients with MO harbouring EXT1 mutations sustain more severe ulnar drift deformities than those with EXT2 mutations.     

Pharmacokinetics and boron uptake of BSH (Na2B12H11SH) in patients with intracranial tumors

We evaluated retrospectively the pharmacokinetics and boron uptakeof BSH (mercaptoundecahydrododecarborate) for Boron Neutron Capture Therapy(BNCT) in 123 patients undergoing craniotomy for intracranialtumors. The pharmacokinetics revealed that BSH could moveeasily from blood to the peripheral organs; itwas retained there and elimination was very slow.BSH after intra-arterial infusion (IA) was found tomove into the peripheral organs more easily thanafter intra-venous (IV) infusion.In patients with malignant glioma, the average valuesof boron concentration in tumor and the tumorto blood ratio (T/B ratio) after IA infusionwere 26.8 ± 19.5 g/g (range, 6.1–104.7 g/g)and 1.77 ± 1.30 (range, 0.47–6.65) respectively. Onthe other hand, after IV infusion the valueswere 20.9 ± 12.2 g/g (range, 7.0–39.7 g/g)and 1.30 ± 0.65 (range, 0.61–2.94) respectively. Thedifferences are not statistically significant. Boron uptake inmalignant glioma was about three times higher thanlow grade glioma. We found a good correlationbetween boron uptake and time interval from BSHinfusion, and 15–20 hours after BSH infusion theboron concentration in tumor was above 20 g/g¹⁰B in 69% of the malignant glioma patients;T/B ratio was above one in 75%, andabove two in 44% of them.We recommend intra-venous infusion of BSH clinically sinceit is safer, and results in sufficient boronconcentration in tumor, and the planned irradiation mightbe optimal around 15–20 hours after the BSHinfusion for treating malignant glioma.