Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporin (CsA) is a potent modulator of multidrug resistance (MDR) and has been combined with etoposide (VP-16) to purge MDR leukemic cells from human bone marrow (BM) in vitro. We studied the feasibility of this approach in an in vivo model for autologous BM transplantation using the murine leukemia cell line P388 and its MDR variant P388/ADR. Colony-forming assays with 2-h drug exposure revealed a tumor selectivity of VP-16 for P388 cells compared to normal murine marrow granulocyte-macrophage colony-forming units (CFU-GM), whereas P388/ADR cells were resistant to VP-16. Simultaneous incubation with CsA restored sensitivity in these cells. Almost 4 logs of cell kill were achieved by treating P388/ADR cells with 60 microM VP-16 plus 2.5 microM CsA (combination A) or 40 microM VP-16 plus 10 microM CsA (combination B), whereas there was a 2.5-log reduction of CFU-GM at these doses. Even though the myelotoxicity of VP-16 was increased by the addition of CsA, this effect was nonspecific as shown by a similar chemosensitization in sensitive P388 as well as in P388/VP 2.5 cells, an atypical MDR variant lacking P-glycoprotein. In vivo experiments addressed the ability of BM treated with VP-16 and CsA to rescue lethally irradiated mice and to purge leukemic cells. In total, 1/14 lethally irradiated mice died due to sepsis within 10 days after receiving 15 x 10(6) BM cells treated ex vivo with combination A in contrast to 1/4 for combination B. All 16 surviving animals demonstrated long-term engraftment. When simulated remission marrow contaminated with 0.1% P388/ADR was purged with VP-16 (60 microM) or CsA (2.5 microM) alone, all mice died from leukemia before day 16 after transplantation (median 14.3 and 12.2 days). In contrast, nine of ten animals receiving similar marrow purged with combination A survived > 60 days without any evidence of disease (p < 0.01). We conclude that combining VP-16 and CsA was effective in purging MDR leukemia cells from transplanted BM in this murine model.
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PMID:Use of etoposide in combination with cyclosporin for purging multidrug-resistant leukemic cells from bone marrow in a mouse model. 146 39

A phase II study of acute leukemia with mitoxantrone (MIT) was conducted by the Tokai Blood Cancer Study Group. The drug efficacy was evaluable in 31 cases (14 of ALL and 17 of ANLL) out of 37 entered at 13 institutions. Five cases were for first induction remission and 26 cases for re-induction remission; ages ranged from 7 to 69 (median: 43); 18 males and 13 females. MIT dosage was intravenous injection of 3-6 mg/m2/day X 5 consecutive days as a rule. Of the 14 cases of ALL, 2 achieved CR and 3, PR; the efficacy rate was 36%. Of the 17 cases of ANLL, 4 achieved CR and 3, PR: the efficacy rate was 41%. Of the 5 first induction remission cases, 3 achieved CR, and 1, PR, the efficacy rate being 80%, whereas out of the 26 re-induction remission cases, 3 achieved CR, 5 PR, and the efficacy rate was 31%. In 3 of 6 cases of CR, large cumulative doses of anthracyclines such as DNR 140 mg plus ACR 410 mg, DNR 360 mg plus ADR 120 mg plus ADR 120 mg, and DNR 240 mg plus ADR 540 mg, had been administered previously in each case. As to complications, sepsis and other infections were observed at the rates of 15% and 32%, respectively, from which it was inferred that in therapy with mitoxantrone, leukopenia should be observed carefully. The major non-hematological toxicity was gastrointestinal symptoms, but the degree was mild. From the results of this trial, it was concluded that mitoxantrone was an effective form of therapy for acute leukemia. Further clinical trials on mitoxantrone in combination with other drugs are scheduled.
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PMID:[Phase II study of mitoxantrone in patients with acute leukemia]. 374 Aug 58

The effects of combination chemotherapy including mitoxantrone (MXN) "M-VEMFH" for advanced breast cancer were studied. The M-VEMFH regimen consisted of MXN 7 mg/m2, VCR 0.7 mg/m2, EX 333 mg/m2, MTX 13.3 mg/m2 i.v. on day 1, 5-FU 333 mg/m2 i.v. from day 1 to day 5 and pred. (H) 60 mg/m2 p.o. with tapering off in 2 weeks. In 7 cases heavily pretreated with combination chemotherapy including ADR, CR 2, PR 2, NC 2 and PD 1 were observed (response rate 57.1%). In 5 cases without prior ADR, PR 1, NC 2 and PD 2 were obtained. One case given 586 mg/m2 of prior ADR died of congestive heart failure after administration of 47 mg/m2 of NXN. One case died of sepsis. The other side effects were stomatitis, vulvitis, abnormal gustation, nausea, vomiting and alopecia. M-VEMFH is effective combination chemotherapy for advanced breast cancer resistant to ADR, but care must be exerted due to the accompanying cardiotoxicity and leukopenia.
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PMID:[Effects of combination chemotherapy M-VEMFH including mitoxantrone in advanced breast cancer]. 405 16

Osteosarcoma is one of the most common juvenile malignant tumors in Korea. Combined modality treatment (pre-operative chemotherapy + limb salvage surgery + adjuvant therapy) improved the patients' overall survival and quality of life. We evaluated the efficacy and feasibility of pre-operative chemotherapy with intra-arterial (IA) cisplatin plus continuous intravenous infusion (CI) of adriamycin. We assessed the rate of limb salvage, recurrence pattern and the survival impact based on the histologic response of pre-operative chemotherapy. Fourty-one patients with histologically-proven high grade osteosarcoma of the extremities were enrolled from January 1990 to June 1995. Pre-operative chemotherapy, cisplatin 120 mg/m2 IA and adriamycin 75 mg/m2/72 h CI was administered every 3 weeks for 3 cycles, followed by limb salvage surgery if possible or by amputation. According to the histologic tumor response, if the tumor necrosis was >90%, the same regimen was administered for 3 cycles as an adjuvant therapy. A salvage regimen (Ifosfamide 7.5 gm/m2/5 d IV + high dose MTX 10 gm/m2 IV+VP-16 360 mg/m2/3 d IV) was administered every 3 weeks for 6 cycles if the tumor necrosis was <90%. Of 41 patients, 37 patients were evaluable for efficacy and toxicities, because 4 patients refused chemotherapy after 1 or 2 cycles. Twenty-one patients were male and 16 were female with median age of 16 years (range 8-41). The tumor locations were: distal femur 20, proximal tibia 8, humerus 6, distal tibia 2 and 1 in proximal femur. All but one patient, who died of neutropenic sepsis, completed the planned pre-operative therapy. Of the 36 patients who received surgery, limb salvage surgery was possible in 30 patients (83.3%) and 27 patients (75%) showed a good response (grade III 10; 27.8%, grade IV 17; 47.2%). With a median follow-up of 23 months, 3-year disease-free survival rate was 54.7% and overall survival rate was 78.3%. Of the 15 patients who recurred, the major metastatic site was the lung. No operation-related mortality was observed. Most patients experienced grade III-IV nausea, vomiting and hematologic toxicities, which were reversible with supportive cares. Pre-operative chemotherapy with IA DDP+CI ADR followed by surgery showed 75% histologic tumor response rate, 83% limb salvage rate and 54.7% 3-year disease-free survival rate with tolerable side effects. To improve the survival rate, the possible role of good salvage chemotherapy with a non-cross resistance regimen in poor responders should be evaluated.
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PMID:Combined pre-operative chemotherapy with intra-arterial cisplatin and continuous intravenous adriamycin for high grade osteosarcoma. 1020 5