Mitomycin resistance in Streptomyces lavendulae includes a novel drug-binding-protein-dependent export system. (1/840)

Sequence analysis of Streptomyces lavendulae NRRL 2564 chromosomal DNA adjacent to the mitomycin resistance locus mrd (encoding a previously described mitomycin-binding protein [P. Sheldon, D. A. Johnson, P. R. August, H.-W. Liu, and D. H. Sherman, J. Bacteriol. 179:1796-1804, 1997]) revealed a putative mitomycin C (MC) transport gene (mct) encoding a hydrophobic polypeptide that has significant amino acid sequence similarity with several actinomycete antibiotic export proteins. Disruption of mct by insertional inactivation resulted in an S. lavendulae mutant strain that was considerably more sensitive to MC. Expression of mct in Escherichia coli conferred a fivefold increase in cellular resistance to MC, led to the synthesis of a membrane-associated protein, and correlated with reduced intracellular accumulation of the drug. Coexpression of mct and mrd in E. coli resulted in a 150-fold increase in resistance, as well as reduced intracellular accumulation of MC. Taken together, these data provide evidence that MRD and Mct function as components of a novel drug export system specific to the mitomycins.  (+info)

Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group. (2/840)

PURPOSE: This phase III study compared docetaxel with mitomycin plus vinblastine (MV) in patients with metastatic breast cancer (MBC) progressing despite previous anthracycline-containing chemotherapy. PATIENTS AND METHODS: Patients (n=392) were randomized to receive either docetaxel 100 mg/m2 intravenously (i.v.) every 3 weeks (n=203) or mitomycin 12 mg/m2 i.v. every 6 weeks plus vinblastine 6 mg/m2 i.v. every 3 weeks (n=189), for a maximum of 10 3-week cycles. RESULTS: In an intention-to-treat analysis, docetaxel produced significantly higher response rates than MV overall (30.0% v 11.6%; P < .0001), as well as in patients with visceral involvement (30% v 11%), liver metastases (33% v 7%), or resistance to previous anthracycline agents (30% v 7%). Median time to progression (TTP) and overall survival were significantly longer with docetaxel than MV (19 v 1 weeks, P=.001, and 1 1.4 v 8.7 months, P=.0097, respectively). Neutropenia grade 3/4 was more frequent with docetaxel (93.1 % v62.5%; P < .05); thrombocytopenia grade 3/4 was more frequent with MV (12.0% v 4.1%; P < .05). Severe acute or chronic nonhematologic adverse events were infrequent in both groups. Withdrawal rates because of adverse events (MV, 10.1%; docetaxel, 13.8%) or toxic death (MV, 1.6%; docetaxel, 2.0%) were similar in both groups. Quality-of-life analysis was limited by a number of factors, but results were similar in both groups. CONCLUSION: Docetaxel is significantly superior to MV in terms of response, TTP, and survival. The safety profiles of both therapies are manageable and tolerable. Docetaxel represents a clear treatment option for patients with MBC progressing despite previous anthracycline-containing chemotherapy.  (+info)

A randomised phase III trial comparing consolidation treatment with further chemotherapy to chest irradiation in patients with initially unresectable locoregional non-small-cell lung cancer responding to induction chemotherapy. European Lung Cancer Working Party. (3/840)

PURPOSE: A phase III randomised trial was conducted in patients with non-metastatic unresectable non-small-cell lung cancer in order to compare, in responders to induction chemotherapy, consolidation treatment by further chemotherapy to chest irradiation. PATIENTS AND METHODS: A total of 462 untreated NSCLC patients were eligible for three courses of induction chemotherapy (MIP) consisting of cisplatin (50 mg/m2), ifosfamide (3 g/m2) and mitomycin C (6 mg/m2). It was proposed that objective responders be randomised to either three further courses of MIP or to chest irradiation (60 Gy; 2 Gy per fraction given over six weeks). RESULTS: An objective response rate of 35% was achieved; 115 patients (including 52% with initial stage IIIA and 44% with initial stage IIIB) were randomised to consolidation treatment, 60 of them to further chemotherapy and 55 to chest radiotherapy. There was no significant difference in survival between the two arms, with a respective median and two-year survival of 42 weeks (95% confidence intervals (95% CI: 35-51) and 18% (95% CI: 8-28) for chemotherapy and 54 weeks (95% CI: 43-73) and 22% (95% CI: 11-33) for irradiation. There was also no statistical difference for response duration between the two arms but chest irradiation was associated with a significantly greater duration of local control than chemotherapy (median duration times: 158 vs. 31 weeks, P = 0.0007). CONCLUSIONS: For non-metastatic unresectable NSCLC treated by an induction chemotherapy regimen containing cisplatin and ifosfamide, if an objective response is obtained, consolidation treatments by further chemotherapy or by chest irradiation result in non-statistically different survival distributions, although a better local control duration is observed with radiotherapy.  (+info)

Phase II trial combining mitomycin with 5-fluorouracil, epirubicin, and cisplatin in recurrent and metastatic undifferentiated carcinoma of nasopharyngeal type. (4/840)

BACKGROUND: This phase-II study was conducted to investigate the potential benefit from the addition of mitomycin to a conventional anthracycline-cisplatin- and 5-fluorouracil-based chemotherapy for recurrent and metastatic undifferentiated carcinoma of nasopharyngeal type (UCNT). PATIENTS AND METHODS: Between July 1989 and December 1991, 44 consecutive patients (M/F 36/8; median age: 45, range 20-72; performance status (PS) 0: 20 patients, PS 1: 14 patients, PS 2: 10 patients) with recurrent or metastatic UCNT were entered in this study after complete clinical, biological, and radiological pre-therapeutic work-ups. Chemotherapy (FMEP regimen) consisted of 800 mg/m2/day 5-fluorouracil in continuous infusion from day 1 to day 4 combined with 70 mg/m2 epirubicin, 10 mg/m2 mitomycin, and 100 mg/m2 cisplatin on day 1, every four weeks for six cycles. Mitomycin was delivered in cycles 1, 3, and 5 only. Eleven patients had isolated loco-regional recurrences, 12 patients had local recurrences associated with distant metastasis, and 21 patients had metastasis only. Toxicity and response were evaluated according to WHO criteria. TOXICITY: Grade 3-4 neutropenia was observed in 122 of 212 evaluable cycles (57%) and 39 of 44 patients (89%); febrile neutropenia occurred in 16 patients (36%) and 24 cycles (11.3%). Grade 3-4 thrombocytopenia was observed in 27 patients (61%) and 45 cycles (21%), including 27 of 45 cycles (60%) with mitomycin. Grade 3 anemia was noted in 18 patients (40%) and 23 cycles (11%), including 18 of 23 cycles (78%) with mitomycin. Grade 3-4 mucositis occurred in 25 cycles (11%) and 14 patients (32%), mainly in those previously treated with radiation therapy in the head and neck area. There were four treatment-related deaths (9%); three of them neutropenia-related, and one of cardiac toxicity. RESPONSE: Forty-four patients were evaluable for response: There were 23 of 44 objective responses (52%), including six complete responses (13%), and 17 partial responses (38%). Additional radiotherapy was given to 13 patients after documentation of response: Nasopharyngeal tumor + cervical nodes (eight patients) and/or on bone metastasis sites (five patients); mediastinal lymph nodes (one patient). At a median follow-up of 87 months (range 71-100), five patients are alive and in continuous complete remission. The median survival time was 14 months and the median time to progression nine months. CONCLUSION: The regimen under study is active in recurrent/metastatic UCNT, but associated with excessive toxicity.  (+info)

Modulating effect of mitomycin or cisplatin on lymphokine-activated killer cell proliferation and antitumor activity to bladder cancer cell lines in vitro. (5/840)

AIM: To study the effect of mitomycin (Mit) or cisplatin (Cis) on the proliferation of lymphokine-activated killer (LAK) cells in patients with transitional cell cancer of bladder and their cytolysis to bladder tumor cells. METHODS: LAK cell proliferation was assayed in the presence of Mit or Cis by cell counting. Bladder cancer cell lines BIU-87 and EJ were cultured as target cells and cytotoxicity of LAK cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The proliferation of LAK cells induced by recombinant interleukin-2 (IL-2) was inhibited by Cis in a concentration-dependent manner and was decreased to 55.3% at 100 mg.L-1 compared with control at 96 h. The enhanced growth of the LAK cells was observed with Mit 5-10 mg.L-1 from 48 to 96 h. Cis 10 mg.L-1 increased the cytotoxicity against BIU-87 and EJ cells. CONCLUSION: Immunomodulatory effect of chemotherapeutic agents on LAK cell proliferation induced by IL-2 in patients with bladder cancer mainly depends on the drug itself.  (+info)

The role of drug transport in resistance to nitrogen mustard and other alkylating agents in L518Y lymphoblsts. (6/840)

An investigation was undertaken of the mechanism of resistance to nitrogen mustard (HN2) and other alkylating agents, with particular emphasis on the interaction between cross-resistance and drug transport mechanisms in L5178Y lymphoblasts. Dose-survival curves demonstrated that the D0 for HN2-sensitive cells (L5178Y) treated with HN2 in vitro was 9.79 ng/ml and the D0 for HN2-resistant cells (L5178Y/HN2) was 181.11 ng/ml; thus, sensitive cells were 18.5-fold more responsive than were resistant cells and the difference was highly significant (p less than 0.001). A similar evaluation of 5 additional alkylating agents, including chlorambucil, melphalan, 1,3-bis(2-chloroethyl)-l-nitrosourea, Mitomycin C, and 2,3,5-tris(ethyleneimino)-1,4-benzoquinone, revealed that L5178Y/HN2 cells were also cross-resistant, in part, to each of these compounds. Furthermore, the degree of cross-resistance was remarkably similar; for each drug, dose-survival studies showed that HN2-resistant cells were approximately 2- to 3-fold more resistant to therapy than were sensitive cells. L5178Y/HN2 cells were also cross-resistant to cyclophosphamide in vivo; after treatment with cyclophosphamide, DBA/2 female mice that were given inoculations of L5178Y cells, but not those given transplants of L5178Y/HN2 cells, showed a significant prolongation of survival time (p less than 0.01). Transport of HN2, hydrolyzed derivative of HN2 and choline by L5178Y lymphoblasts in vitro was not competitively inhibited by any of the other alkylating agents, suggesting that transport of these compounds was by an independent mechanism. These findings suggest that the mechanism whereby L5178Y/HN2 cells are cross-resistant to other alkylating agents may involve nontransport factors and that these other drugs may bypass a major portion of HN2 resistance by using independent transport systems.  (+info)

Induction by alkylating agents of sister chromatid exchanges and chromatid breaks in Fanconi's anemia. (7/840)

Sister chromatid exchanges, which may reflect chromosome repair in response to certain types of DNA damage, provide a means of investigating the increased chromosome fragility characteristic of Fanconi's anemia. By a recently developed technique using 33258 Hoechst and 5-bromodeoxyuridine, it was observed that the baseline frequency of sister chromatid exchanges in phytohemagglutinin-stimulated lymphocytes from four males with Fanconi's anemia differed little from that of normal lymphocytes. However, addition of the bifunctional alkylating agent mitomycin C (0.01 or 0.03 mug/ml) to the Fanconi's anemia cells during culture induces less than half of the increase in exchanges found in identically treated normal lymphocytes. This reduced increment in exchanges in accompanied by a partial suppression of mitosis and a marked increase in chromatid breaks and rearrangements. Many of these events occur at sites of incomplete chromatid interchange. The increase in sister chromatid exchanges induced in Fanconi's anemia lymphocytes by the monofunctional alkylating agent ethylmethane sulfonate (0.25 mg/ml) was slightly less than that in normal cells. Lymphocytes from two sets of parents of the patients with Fanconi's anemia exhibited a normal response to alkylating agents, while dermal fibroblasts from two different patients with Fanconi's anemia reacted to mitomycin C with an increase in chromatid breaks, but a nearly normal increment of sister chromatid exchanges. The results suggest that chromosomal breaks and rearrangements in Fanconi's anemia lymphocytes may result from a defect in a form of repair of DNA damage.  (+info)

Response of remission lymphocytes to autochthonous leukaemic myeloblasts. (8/840)

Thymidine incorporation in vitro by remission lymphocytes from a total of 6 patients with acute myeloid leukaemia (AML) was measured following stimulation by autochthonous and allogeneic AML blasts and cell lines. The early peak response to autochthonous blasts in 2 of these patients (48-72 h) is consistent with the concept of a population of lymphocytes pre-immunized to antigens carried by the blasts. Although stimulation in one patient was increased in the presence of more stimulating (S) blasts than responding (R) lymphocytes, positive responses in other tests were obtained at an S : R ratio of 1 : 1-5. When different methods of treatment of the stimulating autochthonous blasts were compared with untreated cells, mitomycin C gave the highest stimulation indices 2 out of 3 tests. Tissue culture medium in which autochthonous blasts had been incubated for 3-5 days failed to stimulate either remission lymphocytes alone, or combined cultures of lymphocytes with autochthonous or allogeneic blasts, suggesting that mitogenic factors released from autochthonous blasts are not responsible for lymphocyte stimulation. Treatment of autochthonous or allogeneic AML blasts with glycine-HC1(pH 3-0) to remove putative "blocking" factors failed to increase the stimulatory capacity of the leukaemic blasts.  (+info)

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