CHEMOTHERAPY OF ADVANCED MOUSE LEUKEMIA L1210: COMPARISON OF METHOTREXATE ALONE AND IN SEQUENTIAL THERAPY.
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The sequential treatment of mice with advanced leukemia L1210 employing a single injection of 2-chloro-4′,4″-di-2-imidazolin-2-ylterephthalanilide, dihydrochloride (NSC-38280) or cyclophosphamide followed by multiple treatment with methotrexate (MTX) was examined. Mice that received a single injection of NSC-38280 or cyclophosphamide followed by MTX given daily or every 4 days displayed more extensive increases in median survival time than did mice receiving MTX alone on a daily or every-4-day treatment schedule. An initial treatment with either NSC-38280 or cyclophosphamide followed by daily MTX was approximately twice as effective as daily MTX alone, whereas NSC-38280 or cyclophosphamide followed by MTX every 4 days was 3–4 times more effective than MTX alone every 4 days.Keywords:
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Fourteen patients with multiple myeloma resistant to melphalan plus prednisone were treated with BCNU 50 mg/m2 plus cyclophosphamide 200 mg/m2 on day 1, adriamycin 20 mg/m2 on day 2 and prednisone 60 mg orally, daily for days 1 through 5. Therapy was repeated every four weeks. Depending upon criteria used, objective antitumor responses were achieved in five to nine of the 14 patients. Mean survival was 9.5 months and actuarial median survival was 7.0 months. Six patients are alive, four to 35 months after initiation of therapy. This preliminary report indicates that this combination may be a useful treatment program in the management of patients with advanced multiple myeloma. A review of studies employing adriamycin plus BCNU suggests that these regimens currently offer the most effective treatment of melphalan-resistant patients.
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Journal Article Modification of Treatment Schedules in the Management of Advanced Mouse Leukemia with Amethopterin Get access Abraham Goldin, Abraham Goldin Laboratory of Chemical Pharmacology and Biometry and Epidemiology Branch, National Cancer Institute,2Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar John M. Venditti, John M. Venditti Laboratory of Chemical Pharmacology and Biometry and Epidemiology Branch, National Cancer Institute,2Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar Stewart R. Humphreys, Stewart R. Humphreys Laboratory of Chemical Pharmacology and Biometry and Epidemiology Branch, National Cancer Institute,2Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar Nathan Mantel Nathan Mantel Laboratory of Chemical Pharmacology and Biometry and Epidemiology Branch, National Cancer Institute,2Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 17, Issue 2, August 1956, Pages 203–212, https://doi.org/10.1093/jnci/17.2.203 Published: 01 August 1956 Article history Received: 06 April 1956 Published: 01 August 1956
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Seventy-six patients with advanced acute leukemia refractory to conventional chemotherapy were treated with a sequential combination of methotrexate (MTX) and L-asparaginase (L-ASP), based on the reported schedule-dependent synergism between the two drugs in human leukemic cells in vitro. On Day 1, patients received 60 mg/m2 of MTX iv, followed 24 hours later by L-ASP at a dose of 10,000 IU/m2 iv. This sequence was repeated weekly with 50% escalations in the dose of MTX with each course. Overall, 31 of 76 patients (40.7%) achieved complete remission after a median of three courses; the response rate was 35.5% in patients with acute nonlymphocytic leukemia (21 of 59 patients) and 58.8% in patients with acute lymphocytic leukemia (ten of 17). Increasing the starting dose of MTX to 200 mg/m2 did not improve the response rate. Maintenance therapy with the same combination given every 2 weeks produced a median complete remission of 10 weeks. Toxicity was manifested by: acute hypersensitivity reactions to L-ASP (five patients), stomatitis (36 patients), and mild liver abnormalities (five patients). MTX in doses up to 200 mg/m2 caused minimal myelosuppression. We conclude that the MTX-L-ASP combination is a well-tolerated, highly effective induction regimen for refractory acute leukemia.
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Forty-eight fully assessable previously treated patients with biopsy-proven recurrent squamous cell carcinoma of the oral cavity were randomized to receive either methotrexate (MTX), 40 mg/m2 iv push weekly, or sequential MTX and 5-fluorouracil (5-FU) (MTX 150 mg/m2 iv for 1 h; 1 h after the end of MTX, 5-FU 600 mg/m2 iv for 2 h; 24 h later, leucovorin rescue 10 mg/m2 iv and the same dose was given orally every 6 h 4 times; the treatment was repeated every 10 days). There were 1 complete response (CR) and 5 partial responses (PR) in the MTX group; median remission duration = 84 days. There were 3 CR and 11 PR in the MTX-5-FU group (overall response 14/24, 58.3%--p less than 0.05); median remission duration = 125 days. Median survival was 6.2 months in the MTX group and 8.1 months in the MTX-5-FU group. There was no difference in mucositis between the two groups, and a prevalence of leukopenia and moderate gastro-intestinal toxicity in the MTX-5-FU group.
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10-Ethyl-10-deazaaminopterin (EDX, edatrexate) exhibits therapeutic activity against methotrexate (MTX)-resistant tumors in animals and patients. In an effort to improve its efficacy among more chemoresistant tumors, studies were initiated in murine models of advanced metastatic disease comparing EDX and MTX at their maximum tolerated dose alone and in a high-dose regimen incorporating low-dose, delayed Ca leucovorin (LCV) rescue. Both twice-weekly x 3 and weekly x 3 schedules of administration were used with LCV given 16, 20, and 24 h after EDX. The LCV dose required to protect mice was 1/40 and 1/20 of the EDX or MTX dose, respectively, on either schedule. Therapy was initiated 5 or 6 days following i.v. implant of 5 x 10(5) cells of the E0771 mammary adenocarcinoma, T241 fibrosarcoma, Lewis lung carcinoma, B16 melanoma, or C38 colon carcinoma. MTX was essentially ineffective (increase in life span = < 30%) when given alone and either ineffective or only modestly effective (increase in life span = 20-80%) in increasing survival when given in the high-dose regimen to tumor-bearing mice. EDX alone was more effective than MTX when it was given in either regimen of therapy. Also, EDX given in the high-dose regimen (either twice-weekly or weekly x 3) was markedly more effective than EDX alone. Increased survival with this regimen was 2-3-fold greater than EDX alone against all 5 tumors, and long-term survivors were obtained with E0771 (20%), T241 (30-40%), Lewis lung (10-15%), B16 (20%), and C38 (40%) tumors. The administration of 6 doses rather than 3 doses on the twice-weekly schedule against T241 and Lewis lung tumors required a modest increase in the LCV dose but substantially improved efficacy, with as much as 70% long-term survivors (T241 tumor). We conclude that the use of a high-dose regimen with delayed LCV rescue markedly improved the therapeutic effectiveness of EDX against advanced metastatic disease in tumor-bearing mice. These studies should provide a framework for further clinical work with EDX, using this modality of therapy.
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The semisynthetic podophyllotoxin derivative VP-16-213 (NSC 141540) has been evaluated in a phase II study in patients with small cell anaplastic carcinoma of the lung. The drug was administered as an oral solution, the drinking ampoule, in doses of 100 mg twice a day for 4 days in 30 patients previously treated with intensive combination chemotherapy and for 5 days in 10 untreated patients. The courses were repeated every third week with dose modifications according to individual tolerance. All patients had measurable disease and objective responses were obtained in 20 patients (50%), 15 previously treated (50%) and 5 untreated patients (50%). The median time for response after the start of treatment was 15 days (range 6-42) and the median duration of response was 56 days (range 16-147). Dose-limiting toxicity was principally hematologic, consisting of leukopenia, but gastrointestinal toxicity and alopecia were also observed. The study demonstrated that VP-16-213 administered as an oral solution is highly effective against small cell anaplastic carcinoma of the lung without clinical cross-resistance to CCNU, cyclophosphamide, methotrexate, or vincristine.
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Thirteen anticancer agents, ten dual-agent combinations and five three-drug combinations were tested for treatment of L1210 leukemia in dBA/2-J mice. Data obtained form each three-drug regimen were compared with those obtained after administration of each drug alone and each two-drug combination. Cure (greater than 60 days survival) was observed in most of animals treated with VP-16 213 and VM-26. Certain regimens produced 90-100% cure rates (cyclophosphamide plus VP-16 213 or cytosine arabinoside). Inclusion of second or third agent in the treatment schedules produced improvement, deterioration or no effect on median survival time and cure rates, depending on the choice and sequences of evaluated agents. Eighty per cent of mice inoculated even with 10(7) L1210 can be cured by administration of modified schedule of VP-16 213 plus cyclophosphamide.
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