Protective effects of Acanthopanax senticosus - Ligustrum lucidum combination on bone marrow suppression induced by chemotherapy in mice.

This study investigated the combination effects of the Acanthopanax senticosus - Ligustrum lucidum (AS-LL) herb pair on bone marrow suppression caused by chemotherapy. A bone marrow suppression model was established by intraperitoneal injection (i.p.) of cyclophosphamide (CTX, 100 mg/kg). The changes in chemical composition between the AS-LL decocted together and single were analyzed, and their effects on the bone marrow nucleated cells, peripheral blood, thymus and spleen indices, in vitro hematopoietic cell culture, ELISA and cell cycle were detected. The results showed that the contents of the main active components, such as salidroside, isofraxidin and specnuezhenide in the sample of AS-LL decocted together, increased significantly compared to singles. Moreover, AS-LL decocted together exhibited a significantly better therapeutic effect on myelosuppression induced by CTX than AS and LL alone. AS-LL decocted together significantly increased the number of bone marrow nucleated cells and displayed a good regulatory effect on peripheral blood (p < 0.01), while significantly increased the thymus index (p < 0.01) and decreased the spleen index (p < 0.01). AS-LL significantly promoted the formation of cell colonies (p < 0.05), the proliferation and differentiation of hematopoietic progenitor cells, and played a positive regulatory role in hematopoietic factors. AS-LL also reduced the proportion of G0/G1 cells, increased the ratio of S and G2/M cells, and increased the cell proliferation index (PI). All these results implied that AS-LL decocted together might be a promising food additives and therapeutic agent for myelosuppression induced by chemotherapy.

Effect of Shenfu injection on immune function of mice bearing Lewis lung sarcoma with chemotherapy.

Chemotherapy damages immune system and has a lot of side effects. In this study, we investigate the function of Shenfu injection to reduce these unfavorable effects induced by chemotherapy on mice bearing Lewis lung sarcoma. Mice inoculated with Lewis lung sarcoma cells were divided into five groups: Lewis lung sarcoma control group, cyclophosphamide (CTX) group, and Shenfu injection (high, moderate, and low dose) + CTX group. After a 14-day treatment, the counting of peripheral blood cells, CD3+, CD4+, and CD8+ T lymphocytes were done, immunoglobulin (Ig) was measured, coefficients of spleen and thymus were calculated, and spleen T cell proliferation was evaluated in vitro. The CD4+/CD8+ and CD3+ T cells in high- and moderate-dose Shenfu groups were more than the CTX group (p < 0.05); spleen T cell proliferation of mice in high-dose Shenfu + CTX group is more prominent than the CTX group (p < 0.05); coefficients of spleen and thymus, WBC, and platelet (PLT) counting of mice in the CTX group were lower than control and high and moderate dose Shenfu + CTX groups. The level of serous IgG and IgM of all test groups shows no significant difference. Shenfu injection can improve cellular immune function and reduce myolosuppression of mice delivered with chemotherapy.

Efficacy of radiation countermeasures depends on radiation quality.

The detonation of a nuclear weapon or a nuclear accident represent possible events with significant exposure to mixed neutron/γ-radiation fields. Although radiation countermeasures generally have been studied in subjects exposed to pure photons (γ or X rays), the mechanisms of injury of these low linear energy transfer (LET) radiations are different from those of high-LET radiation such as neutrons, and these differences may affect countermeasure efficacy. We compared 30-day survival in mice after varying doses of pure γ and mixed neutron/γ (mixed field) radiation (MF, Dn/Dt = 0.65), and also examined peripheral blood cells, bone marrow cell reconstitution, and cytokine expression. Mixed-field-irradiated mice displayed prolonged defects in T-cell populations compared to mice irradiated with pure γ photons. In mouse survival assays, the growth factor granulocyte colony-stimulating factor (G-CSF) was effective as a (post-irradiation) mitigator against both γ-photons and mixed-field radiation, while the thrombopoietin (TPO) mimetic ALXN4100TPO was effective only against γ irradiation. The results indicate that radiation countermeasures should be tested against radiation qualities appropriate for specific scenarios before inclusion in response plans.

High-dose radioimmunotherapy combined with extracorporeal depletion in a syngeneic rat tumor model: evaluation of toxicity, therapeutic effect, and tumor model.

BACKGROUND: The aim of the current study was to investigate the possibility of increasing the maximal tolerated dose (MTD) of a tumor-selective radiolabeled antibody when radioimmunotherapy (RIT) is combined with extracorporeal depletion of radioimmunoconjugates from the circulation. Furthermore, the authors evaluated whether this increase in dose improved the therapeutic effect on solid manifest tumors in an immunocompetent animal model. METHODS: Rats were injected with high activities/body weight of lutetium ((177)Lu)- or yttrium ((90)Y)-labeled antibody conjugates (monoclonal antibody tetraazacyclododecanetetraacetic acid-biotin) and subjected to removal of the conjugate from the circulation by extracorporeal affinity adsorption treatment 24 hours postinjection. Myelotoxicity was assessed by analysis of blood parameters for 12 weeks. The effect of increased doses in combination with extracorporeal affinity adsorption treatment was evaluated with respect to myelotoxicity and therapeutic effect in a syngeneic rat colon cancer model. RESULTS: The MTD of (177)Lu- or (90)Y-labeled immunoconjugates could be increased 2.0x or 1.5x, respectively, when RIT was combined with extracorporeal affinity adsorption treatment. All animals treated with (177)Lu- or (90)Y-labeled antibodies showed persistent complete response of manifest tumors (approximately 10 x 15 mm) within 16 days postinjection. However, several animals showed disseminated disease 1.5 to 3 months postinjection. CONCLUSIONS: Extracorporeal affinity adsorption treatment is a method that safely and efficiently reduces myelotoxicity associated with RIT. Extracorporeal affinity adsorption treatment allows increased administered activity without increased toxicity, with the aim of increasing the absorbed dose to the tumor. However, because tumor/normal tissue radiosensitivity ratios are more favorable in rodents, it is not possible to draw any conclusions concerning the therapeutic efficacy of increased administered activity in combination with extracorporeal affinity adsorption treatment in this study. Targeted RIT with beta-emitting radionuclides seems not to be effective in microscopic disease, because metastases developed at sites without previously known disease.

Myelophil, a mixture of Astragali Radix and Salviae Radix extract, moderates toxic side effects of fluorouracil in mice.

AIM: To evaluate the efficacy of Myelophil, an extract containing Astragali Radix and Salviae Radix, for reducing complications induced by 5-fluorouracil (5-FU) in a gastrointestinal cancer model. METHODS: We injected 5-FU into mice and then administered Myelophil to examine the ability of the drug to treat the side effects of 5-FU in mice. Peripheral blood counts, histological examinations, and colony-forming assays of bone marrow were conducted, followed by swimming tests and assessment of survival times. RESULTS: Myelophil restored red and white blood cells and platelets in blood, and recovered cell density in bone marrow to levels comparable to those observed within the control group. In addition, Myelophil significantly increased colony-forming unit granulocyte-macrophage (CFU-GM) and CFU-erythroid (CFU-E) compared to the control group. We confirmed that interleukin-3 gene expression was upregulated by Myelophil in spleen cells. Myelophil administration also doubled the survival rate of mice that were severely myelosuppressed as a result of 5-FU injection at a lethal dose of 70%. Finally, the swimming performance of mice significantly improved as a result of Myelophil treatment. CONCLUSION: These results provide experimental evidence in support of clinical applications of Myelophil to minimize 5-FU-induced myelosuppression and improve general post-chemotherapy health.

Effect of fatty acids on bone marrow lesions and knee cartilage in healthy, middle-aged subjects without clinical knee osteoarthritis.

OBJECTIVE: There is evidence that omega-3 polyunsaturated fatty acids alleviate the progression of osteoarthritis (OA). However, little work has been done to investigate the effect of fatty acids on bone marrow lesions and knee cartilage in healthy subjects. We examined this in a cohort of healthy middle-aged subjects without clinical knee OA. METHODS: Two hundred and ninety-three healthy adults without knee pain or injury were recruited from an existing community-based cohort. Intakes of fatty acids and food sources of these were estimated from a food frequency questionnaire at baseline. Tibial cartilage volume, tibial plateau bone area, tibiofemoral cartilage defects and bone marrow lesions were assessed approximately 10 years later using magnetic resonance imaging. RESULTS: In multivariate analyses, higher intakes of monounsaturated fatty acids (OR=2.14, 95% CI 1.04-4.39, P=0.04), total (OR=1.77, 95% CI 1.13-2.77, P=0.01) and n-6 polyunsaturated fatty acids (OR=1.69, 95% CI 1.10-2.61, P=0.02) were associated with an increased risk of bone marrow lesions. Intake of fatty acids was not significantly associated with cartilage volume or cartilage defects. CONCLUSION: These findings support the dietary recommendation towards a shift to foods rich in n-3 polyunsaturated fatty acids in order to maintain an optimal balance between dietary n-3 and n-6 polyunsaturated fatty acids, which is also important in the prevention of atherosclerosis. Although our findings will need to be confirmed in longitudinal studies, they suggest the potential of fatty acids to adversely effect the knee joint.

Protection against radiation induced hematopoietic damage in bone marrow of Swiss albino mice by Mentha piperita (Linn).

The protective effects of Mentha piperita (Linn) extract against radiation induced hematopoietic damage in bone marrow of Swiss albino mice have been studied. Mice were given either double distilled water or leaf extract of M. piperita orally (1 g/kg b.wt./day) once a day for three consecutive days, and after 30 min of treatments on the third day were exposed to 8 Gy gamma radiation. Mice were autopsied at 12, 24, 48 hrs and 5, 10 and 20 days post-irradiation to evaluate the percentage of bone marrow cells, frequency of micronuclei and erythropoietin level in serum. An exposure to gamma radiation resulted in a significant decline in the number of bone marrow cells such as leucoblasts, myelocytes, metamyelocytes, band/stab forms, polymorphs, pronormoblasts and normoblasts, lymphocytes, and megakaryocytes. Pretreatment with leaf extract of M. piperita followed by radiation exposure resulted in significant increases in the numbers of leucoblasts, myelocytes, metamyelocytes, band/stab forms, polymorphs, pronormoblasts and normoblasts, lymphocytes, and megakaryocytes in bone marrow as compared to the control group. Pretreatment with leaf extract of M. piperita followed by radiation exposure also resulted in significant decreases in micronucleus frequencies in bone marrow of Swiss albino mice. A significant increase in erythropoietin level was observed at all the studied intervals in leaf extract of M. piperita pretreated irradiated animals as compared to control animals (radiation alone). The results of the present investigation suggest the protective effects of leaf extract of M. piperita against radiation induced hematopoietic damage in bone marrow may be attributed to the maintenance of EPO level in Swiss albino mice.

The influence of active hexose correlated compound (AHCC) on cisplatin-evoked chemotherapeutic and side effects in tumor-bearing mice.

Cisplatin (cis-diaminedichloroplatinum (II) or CDDP) (a widely used platinum-containing anticancer drug) is nephrotoxic and has a low percentage of tolerance in patients during chemotherapy. The active hexose correlated compound (AHCC) is an extract of Basidiomycotina marketed as a supplement for cancer patients due to its nutrients and fibre content and its ability to strengthen and optimize the capacity of the immune system. The possibility that AHCC could reduce the side effects of cisplatin was assessed in the tumor-bearing BALB/cA mice on the basis of the ability to ameliorate the cisplatin-induced body weight loss, anorexia, nephrotoxicity and hematopoietic toxicity. Although cisplatin (8 mg/kg body weight) reduced the size and weight of the solid tumors, supplementation with AHCC significantly enhanced cisplatin-induced antitumor effect in both the size (p<0.05) and weight (p<0.05). Food intake in the cisplatin-treated mice were decreased following commencement of treatment and this remained low compared with the cisplatin-untreated group (control) throughout the experiment period. Supplementation with AHCC increased the food intake in the cisplatin-treated mice. The blood urea nitrogen and serum creatinine concentrations, and the ratio of blood urea nitrogen to serum creatinine were significantly increased in the cisplatin alone treated group compared to the control group. Their increased levels were mitigated by supplementation with AHCC (100 mg/kg body weight) in the cisplatin-treated group. AHCC was also able to modulate the suppression of bone marrow due to cisplatin and the improvement was statistically significant. The histopathological examination of the kidney revealed the presence of cisplatin-induced damage and this was modulated by AHCC treatment. The potential for AHCC to ameliorate the cisplatin-evoked toxicity as well as the chemotherapeutic effect could have beneficial economic implications for patients undergoing chemotherapy with cisplatin.

Protection against radiation-induced bone marrow and intestinal injuries by Cordyceps sinensis, a Chinese herbal medicine.

Bone marrow and intestinal damage limits the efficacy of radiotherapy for cancer and can result in death if the whole body is exposed to too high a dose, as might be the case in a nuclear accident or terrorist incident. Identification of an effective nontoxic biological radioprotector is therefore a matter of some urgency. In this study, we show that an orally administered hot-water extract from a Chinese herbal medicine, Cordyceps sinensis (CS), protects mice from bone marrow and intestinal injuries after total-body irradiation (TBI). CS increased the median time to death from 13 to 20 days after 8 Gy TBI and from 9 to 18 days after 10 Gy TBI. Although CS-treated mice receiving 10 Gy TBI survived intestinal injury, most died from bone marrow failure, as shown by severe marrow hypoplasia in mice dying between 18 and 24 days. At lower TBI doses of 5.5 and 6.5 Gy, CS protected against bone marrow death, an effect that was confirmed by the finding that white blood cell counts recovered more rapidly. In vitro, CS reduced the levels of free radical species (ROS) within cells, and this is one likely mechanism for the radioprotective effects of CS, although probably not the only one.

Raloxifene attenuation of methotrexate cytotoxicity in human bone marrow by sequence-dependent administration of raloxifene, 5-FU/methotrexate.

BACKGROUND: Increasing evidence suggests that adjuvant systemic chemotherapy is necessary for the survival of breast cancer patients. Antitumor agents are more effective when used in combination with drugs exhibiting different mechanisms of action than when used alone. Previous studies from this laboratory have shown that raloxifene (RAL) attenuation of 5-fluorouracil/methotrexate (5-FU/MTX) cytotoxicity to breast cancer cells was sequence-dependent. The aim was to evaluate the same combination of RAL, 5-FU and MTX to determine the most effective regimes and cellular mechanisms of action to mitigate MTX cytotoxicity in human bone marrow cells. MATERIALS AND METHODS: The sequence-dependent interaction among MTX, 5-FU and RAL on the proliferation and viability of human bone marrow HS-5 cells was determined by the MTT assay and the Trypan blue dye exclusion assay by exposing the cells to MTX, 5-FU and RAL alone, RAL 24 h prior to 5-FU followed 2 h later by MTX, and 5-FU 2 h prior to MTX followed 24 h later by RAL. The control cells were untreated. RESULTS: The growth rate in MCF-7 in early RAL was 68 +/- 3.07% and late RAL 37 +/- 2.05% of the control rate, whereas in bone marrow the same drug combinations exhibit a significant protection against MTX cytotoxity, with the early RAL combination yielding 81 +/- 3.77% and late 54 +/- 2.74% of the control. The finding was further supported by cell flow cytometry and Western blot analysis. CONCLUSION: Sequence-dependent administration of RAL in combination with 5-FU/MTX may have maximum antineoplastic activity in breast cancer while at the same time provide protection to human bone marrow.

[Rhythm of expression of BCL-2 protein of MA13/C mammaryadenocarcinoma bearing-mice]. / Rythme d'expression de la protéine BCL-2 chez la souris porteuse de l'adénocarcinome mammaire MA13/C.

We previously demonstrated a circadian rhythm in response to docetaxel chemotherapy in C3H/HeN mice bearing MA13/C mammary adenocarcinoma. We investigated the relation between this rhythm and the expression of BCL-2 in bone marrow and in tumor tissues. A circadian rhythm characterized BCL-2 expression in the bone marrow, which was hardly modified in tumor-bearing animals. BCL-2 acrophase coincided with the time of highest docetaxel tolerability and efficacy in this model. This suggests that BCL-2 protects the bone marrow from the drug toxicity, especially during the light phase.

The chemokine CCL21 protects normal marrow progenitors from Ara-C cytotoxicity.

PURPOSE: Chemokines are a family of small proteins that regulate leukocyte infiltration into inflamed tissue and play key roles in the pathogenesis of many diseases. Some chemokines can also reversibly inhibit the proliferation of hematopoietic progenitors. We have previously found that the chemokine CCL21 (Exodus-2/SLC/6Ckine/TCA4) is a potent inhibitor of the proliferation of normal hematopoietic progenitors. In this study we sought to determine whether this inhibition of proliferation could be therapeutically exploited by protecting normal marrow progenitors from the cytotoxicity of the S phase-active chemotherapeutic agent Ara-C. METHODS: Untreated and CCL21-pretreated mice were given doses of Ara-C that are toxic to marrow myeloid progenitors. The recovery of these myeloid progenitors was analyzed by colony formation assays. RESULTS: It was found that pretreatment with small doses of CCL21 prevented the death of normal murine marrow progenitors from the toxic effects of Ara-C. CONCLUSIONS: The chemokine CCL21 may be able to prevent Ara-C myelosuppression during acute leukemia induction chemotherapy, and thereby decrease morbidity and mortality of such therapy, and shorten hospital stays.

Phase I study of 90Y-labeled B72.3 intraperitoneal administration in patients with ovarian cancer: effect of dose and EDTA coadministration on pharmacokinetics and toxicity.

The tumor-associated glycoprotein 72 (TAG-72) antigen is present on a high percentage of tumor types including ovarian carcinomas. Antibody B72.3 is a murine monoclonal recognizing the surface domain of the TAG-72 antigen and has been widely used in human clinical trials. After our initial encouraging studies (M. G. Rosenblum et al., J. Natl. Cancer Inst., 83: 1629-1636, 1991) of tissue disposition, metabolism, and pharmacokinetics in 9 patients with ovarian cancer, we designed an escalating dose, multi-arm Phase I study of 90Y-labeled B72.3 i.p. administration. In the first arm of the study, patients (3 pts/dose level) received an i.p. infusion of either 2 or 10 mg of B72.3 labeled with either 1, 10, 15, or 25 mCi of 90Y. Pharmacokinetic studies demonstrated that concentrations of 90Y-labeled B72.3 persist in peritoneal fluid with half-lives >24 h after i.p. administration. In addition, 90Y-labeled B72.3 was absorbed rapidly into the plasma with peak levels achieved within 48 h, and levels declined slowly thereafter. Cumulative urinary excretion of the 90Y label was 10-20% of the administered dose which suggests significant whole-body retention of the radiolabel. Biopsy specimens of bone and marrow obtained at 72 h after administration demonstrated significant content of the label in bone (0.015% of the dose/g) with relatively little in marrow (0.005% of the dose/g). The maximal tolerated dose was determined to be 10 mCi because of hematological toxicity and platelet suppression. This typically occurred on the 29th day after administration and was thought to be a consequence of the irradiation of the marrow from the bony deposition of the radiolabel. In an effort to suppress the bone uptake of 90Y, patients were treated with a continuous i.v. infusion of EDTA (25 mg/kg/12 h x 6) infused immediately before i.p. administration of the radiolabeled antibody. Patients (3 pts/dose level) were treated with doses of 10, 15, 20, 25, 30, 35, 40, or 45 mCi of 90Y-labeled B72.3 for a total of 38 patients. EDTA administration resulted in significant myeloprotection, which allowed escalation to the maximal tolerated dose of 40 mCi. Dose-limiting toxicity was thrombocytopenia and neutropenia. Studies of plasma and peritoneal fluid pharmacokinetics demonstrate no changes compared with patients without EDTA pretreatment. Cumulative urinary excretion of the radiolabel was not increased in patients pretreated with EDTA compared with the untreated group. However, analysis of biopsy specimens of bone and marrow demonstrated that bone and marrow content of the 90Y label was 15-fold lower (<0.001% injected dose/g) than a companion group without EDTA. Four responses were noted in patients who received 15-30 mCi of 90Y-labeled B72.3 with response durations of 1-12 months. These results demonstrate the myeloprotective ability of EDTA, which allows safe i.p. administration of higher doses of 90Y-labeled B72.3 and, therefore, clearly warrant an expanded Phase II trial in patients with minimal residual disease after standard chemotherapy or for the palliation of refractory ascites.

Prevention by carp extract of myelotoxicity and gastrointestinal toxicity induced by 5-fluorouracil without loss of antitumor activity in mice.

The combined effects of 5-fluorouracil (5-FU) and carp (Cyprinus carpio L.) extract on antitumor activity, myelotoxicity and gastrointestinal toxicity were examined in sarcoma 180-bearing mice. Carp extract was found to prevent the occurrence of myelotoxicity as determined by the reduction of leukocyte number, and of gastrointestinal toxicity, as determined by the reduction of small intestinal weight, induced by 5-FU without loss of the antitumor activity of 5-FU.

Phase I and pharmacokinetic study of weekly 5-fluorouracil administered with granulocyte-macrophage colony-stimulating factor and high-dose leucovorin: a potential role for growth factor as mucosal protectant.

Diarrhea is dose-limiting with weekly 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been associated with a decrease in chemotherapy-associated mucosal toxicity. This study was conducted to determine the maximum tolerated dose (MTD) of weekly 5-FU when administered with GM-CSF and high-dose LV. Patients were treated with intravenous LV 500 mg/m2 plus 5-FU weekly for six doses followed by a 2-week rest. GM-CSF 250 mg/m2 was administered subcutaneously 5 days each week. Cohorts were treated with 5-FU at 600, 700, and 800 mg/m2 weekly. Twenty-nine patients were treated. The MTD of 5-FU in this schedule was 700 mg/m2/week, with diarrhea dose-limiting. 5-FU delivered dose intensity at the MTD was 424 +/- 23.7 mg/m2/week, including rest periods. 5-FU and LV pharmacokinetics were not altered by concurrent treatment with GM-CSF. In a weekly schedule with high-dose LV and GM-CSF, the MTD of 5-FU and 5-FU delivered dose intensity were higher than previously reported with 5-FU and LV administered without GM-CSF.

Effect of the immunomodulator AS101 on chemotherapy-induced multilineage myelosuppression, thrombocytopenia, and anemia in mice.

The immunomodulator AS101 has previously been found to induce mouse and human hematopoietic cells to secrete cytokines such as interleukin-1 alpha (IL-1 alpha), IL-2, tumor necrosis factor-alpha (TNF-alpha), and gamma interferon (IFN-gamma). The compound was shown to protect mice from lethal and sublethal effects of chemotherapy and irradiation. AS101 prevented the decrease in the number of bone marrow (BM) and spleen myeloid progenitor cells, and increased the survival of lethally treated mice. In this study, we show a dose-dependent response of AS101 in the induction of high secretion levels of IL-6, IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF). Since these growth factors are known to induce the proliferation and differentiation of multilineage progenitors, including megakaryocytic and erythroid progenitors, we designed this study to evaluate the role of AS101 in attenuating thrombocytopenia, anemia, and multilineage myelosuppression associated with chemotherapy. We demonstrate that pretreatment of mice with AS101 24 hours before intraperitoneal injection of 250 mg/kg cyclophosphamide (CYP) or intravenous injection of 150 mg/kg 5-fluorouracil (5-FU) significantly increased the number of circulating white blood cells (WBC) and platelets. The numbers of both neutrophils and lymphocytes were significantly increased in AS101-treated mice subjected to chemotherapy. In addition, AS101 attenuated erythropenia caused by 5-FU. It could also increase megakaryocyte and erythroid progenitor cells (CFU-MK and CFU-E) in the BM of treated mice severely affected by chemotherapy. We demonstrate that the protective effect of AS101 could be abrogated by treatment with anti-IL-1R or anti-SCF antibodies. We suggest that the endogenous production of cytokines such as IL-1, IL-6, IL-3, SCF, and GM-CSF in mice treated with AS101 offers protection to circulating blood elements and ameliorates the reconstitution of megakaryocytic and erythroid progenitors. The simultaneous protection by AS101 of multilineage cell compartments is probably due to stimulation by AS101 of a selective subpopulation of primitive stem cells resistant to chemotherapy. On the basis of these studies, phase II clinical trials with patients treated with chemotherapy in combination with AS101 have been initiated.

Protective effect of juzen-taiho-to against carboplatin-induced toxic side effects in mice.

The effect of an oral treatment with the Kampo formulation Juzen-taiho-to on the toxicity caused by the intraperitoneal administration of 15 mg/kg carboplatin (CBDCA) 9 times (on days 3, 4, 5, 6, 7, 8, 10, 11 and 12) was examined in ddY mice, which were subcutaneously inoculated with sarcoma 180 (S-180) cells on day 1. White blood cell counts, platelet counts, bone marrow cell counts, relative spleen and thymus weight, food intake and body weight decreased significantly, to about 29%, 13%, 14%, 59%, 36%, 42% and 72% of the control levels, respectively, and serum glutamic-oxaloacetatic transaminase, serum glutamic-pyruvic transaminase and relative stomach weight increased significantly, to about 4, 6 and 3 times the control levels, respectively, by the treatment with CBDCA. However, the blood urea nitrogen and serum creatinine were only slightly increased compared to the control value. Co-treatment with 1.7 g/kg of a lyophilized water extract of Juzen-taiho-to once a day 12 times (on days 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14 and 15) prevented both the decreases and increases caused by CBDCA to near the control levels without reducing the antitumor activity of CBDCA against S-180. The inhibitory effect of Juzen-taiho-to against CBDCA-induced myelosuppression was similar to that against 3.0 mg/kg cisplatin (CDDP) 9 times, while CBDCA-induced myelosuppression was more serious in comparison with CDDP. Therefore, these findings indicate that Juzen-taiho-to could be an effective drug for protecting against the side effects induced by CBDCA in the clinic as well as by CDDP.

The tolerance for zidovudine plus thrice weekly or daily trimethoprim-sulfamethoxazole with and without leucovorin for primary prophylaxis in advanced HIV disease. California Collaborative Treatment Group.

PURPOSE: Trimethoprim-sulfamethoxazole (TMP/SMX) is the preferred agent for prophylaxis of Pneumocystis carinii pneumonia (PCP) in patients with HIV infection, but frequent adverse events limit its usefulness. Intermittent dosing and supplementation with leucovorin have been tried in attempts to improve tolerance. We evaluated these strategies in persons with advanced HIV disease. METHOD: One hundred seven patients were enrolled. All had HIV infection, < 200 CD4+ lymphocytes per mm3, and no history of PCP. Fifty-two were randomized to TMP/SMX twice daily (BID); of these, 26 were randomized to leucovorin with each dose. Fifty-five patients were randomized to TMP/SMX (BID) 3 times per week; of these, 27 were randomized to leucovorin with each dose. All patients took zidovudine concurrently. RESULTS: The 24-week risk of discontinuation due to protocol-defined limiting toxicity was 24% with thrice-weekly TMP/SMX versus 42% with daily TMP/SMX (risk ratio 0.4; 95% CI 0.2 to 1.0). The risks of discontinuation for any reason were 41% and 59% (risk ratio 0.4; 95% CI 0.2 to 0.8). Clinical toxicity, such as headache and gastrointestinal distress, accounted for the observed difference in tolerance between dosing regimens. The 24-week risk of discontinuation due to protocol-defined toxicity was 33% in both the leucovorin and non-leucovorin groups (risk ratio 1.1; 95% CI 0.5 to 2.5). The risks of discontinuation for any reason were 53% and 47% (risk ratio 0.8; 95% CI 0.3 to 1.7). CONCLUSION: Intermittent therapy with TMP/SMX BID thrice weekly is better tolerated than daily BID therapy. Leucovorin use does not improve tolerance for chronic TMP/SMX dosing in AIDS, even among patients taking tablets daily.

Improvement of cisplatin toxicity and lethality by juzen-taiho-to in mice.

The effects of oral treatment with 1-, 5-, 10- and 20-fold the usual daily dose of Juzen-taiho-to on the nephrotoxicity, immunosuppression, hepatic toxicity and gastrointestinal toxicity caused by i.p. administration of 3.0 mg/kg cisplatin (CDDP) 9 times (on days 3, 4, 5, 6, 7, 8, 10, 11, and 12) were examined in ddY mice inoculated with sarcoma 180 (S-180) cells on day 1. The increase in blood urea nitrogen, serum creatinine, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminases and relative stomach weight and decrease in white blood cell count, platelet count, relative spleen and thymus weight, food intake and body weight caused by CDDP were inhibited to nearly the control levels without reducing the antitumor activity of CDDP against S-180 by the oral treatment with either 10-fold (1.7 g/kg) or 20-fold (3.4 g/kg) the usual daily dose of Juzen-taiho-to 12 times (on days 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, and 15). All the mice receiving 4.5, 6.0, 7.5, 9.0, and 12.0 mg/kg CDDP died by day 12, while treatment with 3.4 g/kg Juzen-taiho-to efficiently prolonged the survival time. These findings indicate that Juzen-taiho-to may provide protection against most clinical toxicity caused by CDDP, and Juzen-taiho-to may allow us to administer a much higher dose of CDDP in clinical therapy.

Protective effect of sodium L-malate, an active constituent isolated from Angelicae radix, on cis-diamminedichloroplatinum(II)-induced toxic side effect.

The effects of ingredients of Shi-Quan-Da-Bu-Tang (Juzen-taiho-to) on the nephrotoxicity and bone marrow toxicity caused by i.p. administration of 3 mg/kg cis-diamminedichloroplatinum (II) (CDDP) 9 times (on days 3, 4, 5, 6, 7, 8, 10, 11, 12) were examined in ddY mice s.c. inoculated with sarcoma 180 (S-180) cells on day 1. Angelicae Radix showed the strongest protective effect against the toxicity among the ingredients. The ED50 of a water extract of Angelicae Radix was 17.8 mg/kg for nephrotoxicity (indicated by an increase in blood urea nitrogen) and 59.4 mg/kg for bone marrow toxicity (indicated by a decrease in white blood cell count), when it was administered perorally (p.o.) on days, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15. The water extract did not exert any significant effect on the antitumor activity of CDDP. Bioassay-directed fractionation of the water extract resulted in isolation of a constituent having protective effects against the toxicity: sodium L-malate, C4H4Na2O5, was found to exhibit protective effects against both nephrotoxicity (ED50: 0.4 mg/kg, p.o.) and bone marrow toxicity (ED50: 1.8 mg/kg, p.o.), without reducing the antitumor activity of CDDP. These findings indicate that Angelicae Radix and its constituent sodium L-malate could provide significant protection against CDDP-induced nephrotoxicity and bone marrow toxicity without reducing the antitumor activity.