In vitro schedule-dependent interaction between paclitaxel and SN-38 (the active metabolite of irinotecan) in human carcinoma cell lines

Paclitaxel and irinotecan are important new anticancer agents. The combination of these two agents has been considered for use against a variety of advanced solid tumors. Since the schedule-dependent effects of this combination may be crucial to its use, we studied the interaction of paclitaxel and SN-38 (the active metabolite of irinotecan) in various schedules in four human cancer cell lines in culture. Cell growth inhibition after 5 days was determined using an MTT assay. The effects of drug combinations at the IC₈₀ level were analyzed by the isobologram method. Simultaneous exposure to paclitaxel and SN-38 for 24 h produced antagonistic (subadditive and protective) effects in the human lung cancer cell line A549, the breast cancer cell line MCF7, and the colon cancer cell line WiDr, and produced additive effects in the ovarian cancer cell line PA1. Sequential exposure to paclitaxel for 24 h followed by SN-38 for 24 h, and the reverse sequence, produced additive effects in all four cell lines. These findings suggest that sequential administration, not simultaneous administration, may be the appropriate schedule for the therapeutic combination of paclitaxel and irinotecan. Continued preclinical and clinical studies should provide further insights and assist in determining the optimal schedule for this combination in clinical use. Received: 25 February 1997 / Accepted: 6 November 1997     

Prednisolone plus low-dose aspirin improves the implantation rate in women with autoimmune conditions who are undergoing in vitro fertilization

Objective: To evaluate the effect of prednisolone plus low-dose aspirin (PSL/LDA) in women with autoimmune conditions who were enrolled in an IVF-ET program.

Design: A retrospective clinical study.

Setting: In vitro fertilization unit, Niigata University Hospital, Niigata, Japan.

Patient(s): Three hundred seven women who underwent IVF-ET between January 1996 and December 1997.

Intervention(s): Prednisolone (10 mg/d) and aspirin (81 mg/d) were administered to the women with autoantibodies who chose to participate.

Main Outcome Measure(s): Pregnancy and implantation rates with IVF-ET.

Result(s): Women undergoing IVF who had positive antinuclear antibodies, with or without antiphospholipid antibodies, had significantly lower pregnancy and implantation rates than did women without autoantibodies (14.8% versus 21.7% and 6.8% versus 10.4%, respectively). The administration of PSL/LDA to women with antinuclear antibodies significantly improved the outcome of IVF-ET (40.6% pregnancy rate and 20.3% implantation rate).

Conclusion(s): A high proportion of women who are undergoing IVF-ET have autoantibodies, which are associated with poor IVF outcomes. The administration of PSL/LDA to these women may improve their implantation rate.     

Thallium-201 SPECT with triple-headed gamma camera for differential diagnosis of small pulmonary nodular lesion 20 mm in diameter or smaller

AIM: Although thallium-201 (201Tl) has been used for the diagnosis of lung cancer, its detectability of small pulmonary nodules is not known. The aim of this study was to evaluate the ability of 201Tl SPECT for the differential diagnosis for the pulmonary nodules 20 mm in diameter or smaller. METHODS: 201Tl SPECT was performed in 31 patients suspected of having primary lung cancer. The final diagnosis was established by histology, and tumor size was 10 to 20 mm in diameter. Twenty of 31 patients had malignant tumors, including squamous cell lung cancer (n = 5), adenocarcinoma (n = 14) and small cell lung cancer (n = 1), but in none of them was there mediastinal lymphnode involvement. RESULTS: Ten of 20 malignant tumors and 1 of 11 benign lesions demonstrated significant 201Tl uptake, so that the positive predictive value, negative predictive value, sensitivity and specificity for the diagnosis of lung cancer were 90.9% (10/11), 50.0% (10/20), 50.0% (10/20) and 90.9% (10/11), respectively. CONCLUSION: These data suggest that sensitivity for detecting lung cancer 20 mm or less in diameter may be insufficient, but even in patients with small pulmonary nodules, a positive 201Tl result is highly predictive of lung cancer.     

Serine protease inhibitors prevent alcoholic liver injury]

The hepatotoxic effects of alcohol have been described in detail, but factors responsible for its hepatotoxicity have only partially characterized. It now appears that Kupffer cell derived TNF-alpha participates in several aspects of alcoholic liver injury. On the other hand, protease inhibitors have been used successfully for treatment of intractable diseases in which TNF-alpha is involved in the pathogenesis, including ulcerative colitis and Crohn's disease. Here, we will review new evidence for the proposal that serine protease inhibitors prevents alcoholic liver injury via mechanisms dependent on Kupffer cell derived TNF-alpha.     

Vaccination of dendritic cells loaded with interleukin-12-secreting cancer cells augments in vivo antitumor immunity: characteristics of syngeneic and allogeneic antigen-presenting cell cancer hybrid cells.

Cancer immunotherapy by fusion of antigen-presenting cells and tumor cells has been shown to induce potent antitumor immunity. In this study, we characterized syngeneic and allogeneic, murine macrophage/dendritic cell (DC)-cancer fusion cells for the antitumor effects. The results showed the superiority of allogeneic cells as fusion partners in both types of antigen-presenting cells in an in vivo immunotherapy model. A potent induction of tumor-specific CTLs was observed in these immunized conditions. In addition, the immunization with DC-cancer fusion cells was better than that with macrophage-cancer fusion cells. Both syngeneic and allogeneic DC-cancer fusion cells induced higher levels of IFN-gamma production than macrophage-cancer fusion cells. Interestingly, allogeneic DC-cancer fusion cells were superior in that they efficiently induced Th1-type cytokines but not the Th2-type cytokines interleukin (IL)-10 and IL-4, whereas syngeneic DC-cancer fusion cells were powerful inducers of both Th1 and Th2 cytokines. These results suggest that allogeneic DCs are suitable as fusion cells in cancer immunotherapy. To further enhance the antitumor immunity in the clinical setting, we prepared DCs fused with IL-12 gene-transferred cancer cells and thus generated IL-12-secreting DC-cancer fusion cells. Immunization with these gene-modified DC-cancer fusion cells was able to elicit a markedly enhanced antitumor effect in the in vivo therapeutic model. This novel IL-12-producing fusion cell vaccine might be one promising intervention for future cancer immunotherapy.     

Lamivudine treatment in a patient with hepatitis B virus reactivation after allogenic peripheral bone marrow transplantation.

We report the case of a 52-year-old woman with hepatitis B virus (HBV) reactivation during treatment for chronic graft vs. host disease (GVHD) after peripheral bone marrow transplantation (PBSCT) to treat chronic myelocytic leukemia. She was given cyclosporine and prednisolone orally to treat chronic GVHD after PBSCT. Liver dysfunction first developed 25 months after transplantation with the appearance of hepatitis B s antigen (HBsAg), hepatitis B e antigen (HBeAg), and elevation of HBV-DNA up to 4.5 log copies/ml. Retrospective examination of her serum before PBSCT proved negative for HBsAg and HBeAg, and positive for anti-HBsAg, anti-HBeAg, anti-hepatitis B core antigen, and HBV-DNA (2.7 log copies/ml), showing that she was in a state of occult HBV infection. Nucleotide sequences of the HBV genome obtained from her serum showed no core promoter mutations at nt 1762 and 1764 and no pre-core mutation at nt 1896. Polymerase chain reaction-restriction fragment length polymorphism showed that she was infected with HBV genotype B. The administration of lamivudine, a nucleoside analog, improved her liver function and reduced HBV-DNA replication. We conclude that antiviral agents, such as lamivudine, are effective for treating hepatitis B reactivation during immunosuppressive treatment, such as for GVHD. The administration of a nucleoside analog before transplantation should also be considered in the light of HBV genotypes and mutations, even if HBsAg was negative and the viral load was low before transplantation.     

Gender difference in alcoholic liver injury]

Gender differences of alcoholic liver injury have been described previously, but mechanisms have only partially characterized. For example, it is known that females develop alcoholic liver injury more rapidly and to a greater extent than males. It now appears that estrogen participates in several aspects of this phenomenon. On the other hand, attention has been directed towards the effect of ethanol ingestion on Kupffer cell function, which is stimulated by gut-derived endotoxins via mechanisms dependent on increased gut permeability and the possible relationship between Kupffer cell and alcohol-induced liver injury.     

Evaluation of transcutaneous and end-tidal carbon dioxide levels during inhalation sedation in volunteers

Measurement of end-tidal carbon dioxide (P_ETCO₂) is useful because of its noninvasiveness, continuity, and response time when sudden changes in ventilation occur during inhalation sedation. We compared the accuracy of P_ETCO₂ using a nasal mask and nasal cannula with the accuracy of transcutaneous carbon dioxide (TC-CO₂) and determined which method is more useful during inhalation sedation in volunteers. We used a modified nasal mask (MNM) and modified nasal cannula (MNC) for measurement of P_ETCO₂. The capnometer measured P_ETCO₂ in the gas expired from the nasal cavity by means of two devices. The volunteers received supplemental O₂ by means of each device at a flow rate of 6 L/min. After the volunteers lay quietly for 5 min with a supply of 100 % O₂, they received supplemental N₂O by means of each device at concentrations of 10, 20, and 25 % for 5 min and 30 % for 25 min. The correlation coefficient was poorer in the MNM than in the MNC, and the mean difference between TC-CO₂ and P_ETCO₂ in the MNM was greater than that in the MNC. The difference between the TC-CO₂ and P_ETCO₂ ranged from 3 to 6 mmHg in the MNM and from 2 to 5 mmHg in the MNC. The difference between two variables against the TC-CO₂ and the CO₂ waveforms obtained by means of the two devices were within the clinically acceptable range. Our two devices can provide continuous monitoring of P_ETCO₂ with a supply of N₂O/O₂ in patients undergoing inhalation sedation.