Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since 1984, the Respiratory Committee of the Cancer and Leukemia Group B (CALGB) has evaluated carboplatin, either alone or in combination, in five separate phase II studies for patients with inoperable non-small cell lung cancer (NSCLC). All patients had an Eastern Cooperative Oncology Group performance status of 0 to 2 and had not received previous treatment with chemotherapy. In 70 patients with stage IIIB or IV disease, carboplatin 400 mg/m2 administered intravenously once every 4 weeks produced a 16% overall response rate and an acceptable toxicity profile. Subsequently, combinations of carboplatin/cisplatin, carboplatin/etoposide, and carboplatin/vinblastine have been evaluated in similar patient groups. Response rates of 11%, 12%, and 20%, respectively, were obtained. Myelosuppressive toxicity was substantially greater with carboplatin/etoposide and carboplatin/vinblastine than with carboplatin alone. Carboplatin/vinblastine demonstrated efficacy similar to that of the cisplatin/vinblastine combination previously evaluated by CALGB for treatment of similar patients with advanced NSCLC; ease of administration and lack of significant nephrotoxicity also compared favorably with cisplatin-based therapy. In regional NSCLC patients, carboplatin 100 mg/m2/wk can be administered intravenously concurrently with 60 Gy thoracic radiotherapy given over 6 weeks. The impact of concurrent carboplatin added to a sequential chemotherapy-radiotherapy program for patients with regional NSCLC is currently under study by the CALGB Respiratory Committee.
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PMID:Carboplatin in non-small cell lung cancer: an update on the Cancer and Leukemia Group B experience. 132 22

The use of newly developed antileukemic agents is one of the therapeutic options available to overcome clinical resistance in refractory or other high-risk acute leukemias. Carboplatin is a second-generation platinum compound that has demonstrated significant activity against acute leukemia, particularly when administered via continuous intravenous infusion in phase I clinical trials. Based on the preliminary reports of these trials, we designed a phase II clinical trial to evaluate the efficacy and toxicity of carboplatin via continuous infusion (300 mg/m2/d for 5 days) for remission induction in adult patients with high-risk acute leukemia. Because of the significant antileukemic activity and the scarce extrahematologic toxicity noted in this trial, in order to increase the response rate, we were encouraged to try carboplatin in combination in a similar set of patients. A phase II study of carboplatin 300 mg/m2/d for 5 days in combination with etoposide 100 mg/m2/d for 3 to 4 days was designed by our group to treat patients with high-risk acute leukemia. This combination was chosen because (1) each drug has independent activity in acute nonlymphoblastic leukemia (ANLL) and (2) carboplatin/etoposide has been extensively tested in patients with small and non-small cell lung cancer, and therefore the toxicity and maximum tolerated dose are known. The complete remission rate achieved was somewhat higher (40%) than with carboplatin alone despite the increased incidence of extrahematologic toxicities, particularly gastrointestinal bleeding. At present, carboplatin should be considered as a new effective agent for the treatment of ANLL.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Carboplatin alone or in combination in high-risk acute nonlymphoblastic leukemia. 139 Mar 15

Rhizoxin is a 16-membered antifungal macrocyclic lactone isolated from the plant pathogenic fungus Rhizopus chinensis. The compound binds to tubulin, preventing microtubule formation, and inhibiting mitosis. It possesses antitumour activity in vivo against various preclinical murine models, both leukaemias and solid tumours model, as well as in vincristine- and doxorubicin-resistant leukaemia lines. In the present study, cytotoxic activity was observed in human tumour cell lines in vitro at very low concentrations (+/- 10(-10) M) particularly against melanoma, colon, renal, non-small cell and small cell lung cancer. In vivo antitumour activity was demonstrated in murine P388 and L1210 murine leukaemias, solid tumour models B16 melanoma and M5076 sarcoma, and in 5 out of 9 human solid tumour xenografts: LOX melanoma, MX-1 breast cancer, non-small cell lung cancer A549, and small cell lung cancers LXFS 605 and LXFS 650. The absence of cross-resistance to vinca alkaloids was confirmed in vivo against the vincristine-resistant P388 leukaemia subline and the vincristine-resistant human small cell lung cancer LXFS 650. In addition, the antitumour activity of rhizoxin was improved by prolonged or repeated drug administration indicating a schedule dependency. In animal toxicology studies, transient changes in erythrocyte and leukocyte numbers, local phlebitis, diarrhea, and spermatogenic arrest were observed. The LD10 value of rhizoxin after a single intravenous injection was 2.8 mg/kg (8.4 mg/m2). One-tenth of the mouse equivalent LD10 (0.84 mg/m2), the starting dose for clinical phase I studies, was considered to be safe in rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preclinical antitumour activity and animal toxicology studies of rhizoxin, a novel tubulin-interacting agent. 145 59

Between July 2, 1987, and August 21, 1987, Cancer and Leukemia Group B (CALGB) conducted a phase II evaluation of carboplatin (CBDCA) and vinblastine (VBL) in advanced non-small-cell lung cancer. Of the 58 patients who entered the study, 55 were eligible and produced follow-up data. Chemotherapy, which was carried out in 28-day cycles, consisted of 4 mg/m2 VBL given on days 1 and 3 and 125 mg/m2 CBDCA given on days 1-3. Partial responses were observed in 10 cases (18%), and 1 patient (2%) exhibited regression of evaluable disease. No complete responses were achieved. The overall objective response rate was 20%. The median survival was 6.1 months, and the median time to treatment failure was 3.3 months. Life-threatening (grade 4) toxicity was mainly leukopenia (20%), followed by anemia (7%), infection (4%), thrombocytopenia (2%), fever (2%), nausea and vomiting (2%), and weight loss (2%). There were two deaths due to infection. The results of this study demonstrate that the combination CBDCA/VBL is active in advanced NSCLC; however, whether this combination is more active than either CBDCA or VBL alone is unknown.
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PMID:Carboplatin and vinblastine in advanced non-small-cell lung cancer: a phase II study. 166 Mar 54

Vinorelbine is a new 5' nor Vinca alkaloid, active by i.v. route, in various types of cancer disease such as non-small cell lung cancer and advanced breast cancer. In order to evaluate the possibility of using this drug for local treatment of cancer, Vinorelbine-loaded bioresorbable polymeric implants were prepared using a copolymer of D,L-lactic and glycolic acids (PLA 37.5 GA 25). According to the manufacturing process, the 1.2-mm-diameter cylindrical rods obtained had a drug content of 1, 5, or 20% (w/w) and released half of their content within about 6 days in vitro. In vivo release in rats was slower, half of the drug being released after about 14 days. A dose-dependent antitumoral effect was observed in mice (solid P388 leukemia model) when implants were administered into or in contact with the tumor. At highest drug loads and when administered soon after tumor implantation, Vinorelbine implants were more effective than i.v. administration (median survival time of treated animals related to untreated controls, greater than 360 versus 188). In dogs, results of toxicity experiments revealed that administration of implants in vital organs must be avoided. On the contrary, s.c. administration was well tolerated. A transient local necrosis was observed in the days following implantation, but normal skin was recovered after about 10 weeks. Thus, a clinical trial was conducted on patients with head and neck cancer; implantation of 20% loaded polymeric implants into the tumor sites succeeded in 8 of 9 patients. The sole failure was attributed to the unusual hardness of the tumor tissue. Except for a local transient inflammatory reaction (easily treated with nonsteroidal antiinflammatory agents), no other sign of toxicity was detected, and patients tolerated the device well. Fourteen days after implantation, patients underwent their planned surgery, and the implants were recovered. Residual drug content varied from 24 to 55%. In all cases, there was a clearly delimited necrotic area around the implant, ranging from 0.5 to 3.5 cm in diameter. In the smallest tumors, necrosis was also observed in the normal tissue inside this area. These results invite further studies to evaluate such drug-loaded polymeric implants.
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PMID:Experimental studies and preliminary clinical trial of vinorelbine-loaded polymeric bioresorbable implants for the local treatment of solid tumors. 191 58

These pilot trials clearly demonstrate the feasibility of administering neoadjuvant chemotherapy to patients with stage III NSCLC. Response rates in most of these trials reach or exceed 50%, indicating increased activity of chemotherapy in NSCLC when used at an earlier time in the natural history of the disease, as has been shown in other diseases. In addition, histologic confirmation of complete response can occasionally be achieved. Most of the studies reviewed here have included patients with unresectable disease, who would now frequently be classified as stage IIIB. For these patient cohorts the survival data reported are frequently disappointing, suggesting that the high response rates to neoadjuvant chemotherapy do not necessarily translate into improved survival of the patients. On the other hand, where patients with stage IIIA disease were treated and surgery was included in the overall treatment plan, the survival data are more encouraging. Although most chemotherapy regimens have included cisplatin, it is not clear which combination of drugs and which schedules are superior. Clinical research, therefore, clearly needs to continue to focus on the development of innovative drug combinations and the evaluation of new drugs in NSCLC in an attempt to further increase overall and complete response rates to neoadjuvant chemotherapy. At the same time, randomized studies are needed to unequivocally establish whether the addition of neoadjuvant chemotherapy to standard therapy improves survival for stage IIIA and/or stage IIIB NSCLC as compared with standard therapy alone. Results from one such randomized study, which was conducted by the Cancer and Leukemia Group B (CALGB), have recently been reported. One-hundred and eighty patients with unresectable NSCLC were randomized to receive radiotherapy alone or two cycles of cisplatin and vinblastine followed by radiotherapy. One-hundred and fifty-five eligible patients were analyzed for response. Of 77 patients receiving radiotherapy alone, 43% responded, including 16% with a complete response. Of 78 patients receiving neoadjuvant chemotherapy, 56% responded to both treatment modalities, including 19% with complete response. With a median follow-up of 19 months, the median survival was 16.5 months for patients receiving combined modality therapy and 8.5 months for patients receiving radiotherapy alone. The pattern of relapse was identical in both study arms, showing a predominance of local recurrence or of combined local and distant recurrence, whereas few patients experienced distant disease progression alone.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sequential combined modality therapy for stage III non-small cell lung cancer. 196 80

The Cancer and Leukemia Group B (CALGB) utilized a randomized phase II trial design to evaluate two cisplatin-based combinations, cisplatin-cytarabine (ara-C) and cisplatin-vinblastine, in 151 patients with advanced non-small cell lung cancer. Patients entered on study had not received prior chemotherapy. Platinum doses were equivalent in the two treatment programs. The total response rate (complete response, partial response, regression of evaluable disease) for the cisplatin-vinblastine group was 22% (16/73). Failure-free survival at six months for this group was 41%, survival at six months was 63%. The cisplatin-ara-C group had a total response rate of 9% (7/78) with a failure-free survival at six months of 14% and a six-month survival of 47%. Severe or life-threatening toxicity was seen in 73% of cisplatin-vinblastine cases and 59% of cisplatin-ara-C patients. Neither regimen is active enough to warrant designation as "standard therapy" for patients with M1 disease.
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PMID:Platinum-based combination chemotherapy in advanced non-small cell lung cancer: a randomized phase II trial of the Cancer and Leukemia Group B. 215 14

The cytotoxicity of interleukin-2-activated killer (LAK) cells with or without anticancer drugs against cell lines with acquired drug resistance was evaluated in vitro by colony assay. Human non-small cell lung cancer cell lines, PC-9 and PC-14, human leukemia cell line, K-562, and their sublines resistant to cisplatin (CDDP), PC-9/CDDP and PC-14/CDDP, and to adriamycin (ADM), K-562/ADM, were used as target cells. PC-9/CDDP demonstrated a marked increase in susceptibility to killing by both peripheral blood lymphocytes (PBL) and LAK cells, as compared to the parental cell line, PC-9. The cytotoxicity of PBL and LAK cells against PC-14/CDDP and K-562/ADM was similar to that against their parental cell lines. Moreover, the combination of LAK and CDDP had a synergistic effect on PC-14 and PC-14/CDDP.
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PMID:Inhibition of colony formation of drug-resistant human tumor cell lines by combinations of interleukin-2-activated killer cells and antitumor drugs. 249 60

SM-1 is a murine monoclonal antibody strongly reactive with a cell membrane antigen of small cell carcinoma (SCC) of the lung but unreactive with the membrane of most other carcinomas and normal tissues including normal bone marrow. We have found that in the presence of human complement, SM-1 antibody is highly cytotoxic to SCC cells. Using three treatments with antibody and complement, more than 99% of SCC cells in culture were lysed, as determined by the chromium release and clonogenic assays. Similar efficiency of SCC cell lysis was observed when one SM-1 antibody treatment was followed by three treatments with human complement. In contrast, there was little antibody-dependent lysis of non-small cell lung cancer cells, other carcinomas, and leukemia cell lines. The amount of chromium released from normal bone marrow cells treated with SM-1 antibody and complement was minimal and was mainly due to the effect of complement alone. Clonogenic assays, including colony-forming unit-granulocytic/monocytic, erythroid burst-forming unit, and colony-forming unit-granulocytic/erythroid/monocytic/megakaryocytic, also showed no significant SM-1 antibody-dependent cytotoxicity on normal bone marrow precursors. Since SM-1 antibody is selectively cytotoxic to SCC cells in the presence of human complement, it is a potentially useful agent for the selective eradication of tumor cell contamination in marrows of patients with metastatic small cell lung cancer and possibly for in vivo serotherapy.
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PMID:Use of SM-1 monoclonal antibody and human complement in selective killing of small cell carcinoma of the lung. 298 9

During the past two decades a few clinical reports have suggested that the therapeutic efficacy of cyclophosphamide against malignant tumors was partly mediated by drug effects on host immune mechanisms. This action was strictly dose-dependent: immunostimulation was only evident in the low dose range, whereas immunosuppression became significant at intermediate or high doses. In search for an experimental model of the immunoaugmenting effects of oxazaphosphorines it was found that the transplantable leukemia L 5222 of BD IX inbred rats could be cured by low doses of oxazaphosphorines, whereas this therapeutic activity was gradually lost with increasing doses. Dose-response relationship studies with cyclophosphamide and its stabilized 4-hydroxy-derivative mafosfamide showed a bell-shaped pattern. When the two compounds were compared, the immunotherapeutic range of mafosfamide was considerably broader. Further experiments suggested that the oxazaphosphorine effect was T-cell mediated. Treated and surviving animals were immune to additional tumor challenges. It was shown that mafosfamide at low concentrations inhibited preferentially T-suppressor cell proliferation in vitro; in analogy, an elimination of suppressor mechanisms could also be responsible for the in vivo effects. In clinical phase I studies, the maximally tolerated dose of mafosfamide was around 3 g/m2. The presented animal data, however, indicated that the immunopharmacological dose was approximately 10 times lower. Studies for immunotherapy with mafosfamide are currently ongoing in patients with non-small cell lung cancer and other malignant diseases.
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PMID:Oxazaphosphorine effects in L 5222 rat leukemia. 343 88


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