menogaril and Lung-Neoplasms

The treatment of small cell lung cancer (SCLC) has evolved significantly over the past 3 decades. Single-agent and combination chemotherapies given with radiotherapy have greatly improved response rates and median survival. Combination regimens such as cisplatin/etoposide, carboplatin/etoposide, ifosfamide/carboplatin/etoposide, cyclophosphamide/doxorubicin/vincristine, and etoposide/ifosfamide/cisplatin have all achieved good response rates. Improving long-term survival, however, has remained problematic. Treatment with biological response modifiers (interferons alpha and gamma) has not shown promise in this setting. New agents showing good preliminary single-agent activity in untreated SCLC include paclitaxel, vinorelbine, gemcitabine, topotecan, and teniposide. Results obtained with single-agent docetaxel and CPT-11 are thus far inconclusive. Studies evaluating response and survival rates of these new agents in combination with agents of known activity are underway.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Small Cell; Clinical Trials as Topic; Deoxycytidine; Docetaxel; Drugs, Investigational; Gemcitabine; Humans; Immunologic Factors; Irinotecan; Lung Neoplasms; Menogaril; Paclitaxel; Taxoids; Teniposide; Topotecan; Treatment Outcome; Vinblastine; Vinorelbine

Doxorubicin is one of the most potent drugs for the treatment of small cell lung cancer (SCLC), but less potent for non-small eell lung cancer (NSCLC). The prevalent use of doxorubicin is limited by the development of cardiomyopathy. Therefore, TUT-7 SM-5887, and ME2303 have been under the clinical studies to find new anthracyclines with less cardiotoxicity and higher therapeutic indices not only for SCLC but also for NSCLC. The dose-limiting factor of these drugs determined in phase I studies was leukocytopenia. Phase II studies which are currently under way have indicated that SM-5887 is possibly most potent for the treatment of NSCLC, and that these drugs have less cardiotoxicity compared to the mother compound, doxorubicin.

Topics: Anthracyclines; Antibiotics, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Doxorubicin; Female; Humans; Lung Neoplasms; Male; Menogaril

A phase I study with TUT-7, a new anthracycline antitumor antibiotic, was conducted in 35 malignant tumor patients at 11 institutions nationwide. The study was initiated with a single dose at 100 mg/body which was equivalent to 2n, then the dose as escalated up to 700 mg/body in accordance with the modified Fibonacci's scheme. The dose limiting factor (DLF) was considered to be leukopenia, and maximum tolerated dose (MTD) was 700 mg/ body. The consecutive days dosing study subsequently conducted started with 25 mg/body/day, and the dose level was escalated up to 150 mg /body/day. TUT-7 was orally administered for seven (7) to fourteen (14) consecutive days in principle. It was considered that DLF was leukopenia and MTD was 100 mg/body/day for consecutive days dosing. The study indicated that serum drug concentrations reached their plateaus on the 5th day after initiation of TUT-7 treatment and the accumulation of this compound was low. With these findings, a regimen with a dose of 100 mg/body/day orally administered for 14 consecutive days was recommended for early phase II studies.

Topics: Administration, Oral; Aged; Antibiotics, Antineoplastic; Breast Neoplasms; Colonic Neoplasms; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Male; Menogaril; Middle Aged; Neoplasms; Pancreatic Neoplasms

Studies have shown that response to a given chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer is superior to that in patients previously treated with other regimens. This finding raises the question of whether it is necessary and ethical to study the effects of new anticancer agents in untreated patients. Such studies appear to be the best test for drug development, but there has been no evaluation of whether survival of untreated patients, whose cancer is sensitive to established drugs, is adversely affected in trials of new drugs.. This randomized study of untreated patients with extensive-stage small-cell lung cancer was designed (a) to compare the survival of patients treated with either effective standard chemotherapy or an investigational anticancer drug as initial therapy and (b) to evaluate response rates and toxic effects of such therapies.. Eighty-six patients were randomly assigned to receive, as initial therapy, either the standard CAV regimen--cyclophosphamide (1000 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg/m2) every 3 weeks--or the phase II drug menogaril (200 mg/m2) every 4 weeks. Treatment after induction therapy varied, depending on patient response, but nonresponders and those with disease progression received salvage chemotherapy--etoposide (120 mg/m2 on days 1, 2, and 3) and cisplatin (60 mg/m2 on day 1), repeated every 3 weeks.. Of the 43 patients on CAV, 42% responded (eight complete responses and 10 partial responses); 5% of the 43 on menogaril responded (two partial responses) (P = .0001). Twelve (22%) of 54 patients responded to salvage chemotherapy (five complete responses and seven partial responses). Within 3 months from start of treatment, twelve patients died--3 patients in the CAV group and nine patients in the menogaril group (P = .12). The estimated median survival was 37 weeks with menogaril and 45 weeks with CAV (P = .28). At 6 months, survival was 76.7% for the CAV group and 67.4% for the menogaril group. At 12 months, survival rates were 24.4% and 27.9%, respectively. Confidence intervals (95%) for the differences between the proportions surviving in the two groups were -9%-28% at 6 months and -25%-14% at 12 months. Use of CAV resulted in significantly higher occurrence of severe and life-threatening treatment-related complications (P = .002).. The confidence intervals for the differences in survival are too wide to conclude that evaluation of a new drug in untreated patients with extensive-stage small-cell lung cancer is or is not harmful. The data do suggest, however, that use of this study design may have no adverse effect on survival.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cyclophosphamide; Doxorubicin; Drug Evaluation; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Menogaril; Neoplasm Staging; Nogalamycin; Vincristine

Forty-five patients with non-small cell lung cancer were treated in a phase II trial with menogaril 200 mg/m2 IV every twenty-eight days by a one-hour infusion. One partial response was noted while twenty-two patients had stable disease (51%). Progressive disease was noted in the remaining twenty-two patients. There was one fatal complication due to pancytopenia and pneumonia. Otherwise, the drug was reasonably well tolerated. At this dosage and schedule, menogaril has no substantial anti-tumor activity for patients with non-small cell lung cancer.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Evaluation; Female; Humans; Lung Neoplasms; Male; Menogaril; Middle Aged; Nogalamycin

We estimated antitumor activity of TUT-7 following p.o. administration using animal tumor models and human tumor xenografts. In mouse L 1210 leukemia system, antitumor activity of TUT-7 administered orally was as good as that by i.v. administration. Treatment involving schedules of every 4-days or daily administration was much more effective than single treatment. Therapiotic indices of this compound administered both p.o. or i.v. routes, were better than that of adriamycin administered i.v.. TUT-7 showed antitumor activities against various mouse tumors (L 1210 leukemia, P 388 leukemia, colon 38 adenocarcinoma, B 16 melanoma), LX-1 human tumor xenografts, and Yoshida sarcoma in rat. Base on above results, we concluded that oral administration is one of the useful route of TUT-7 administration.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Colonic Neoplasms; Daunorubicin; Doxorubicin; Humans; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Lung Neoplasms; Menogaril; Mice; Nogalamycin; Rats; Sarcoma, Yoshida

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Daunorubicin; Drug Evaluation; Female; Humans; Lung Neoplasms; Male; Menogaril; Middle Aged; Nogalamycin

A multidrug resistant variant (H69AR) of the human small cell lung cancer cell line NCI-H69 was obtained by culturing these cells in gradually increasing doses of Adriamycin up to 0.8 microM after a total of 14 months. H69AR expresses the multidrug resistant phenotype because it is cross-resistant to anthracycline analogues including daunomycin, epirubicin, menogaril, and mitoxantrone as well as to acivicin, etoposide, gramicidin D, colchicine, and the Vinca alkaloids, vincristine and vinblastine. H69AR is also similar to other multidrug resistant cell lines in that it displays little or no cross-resistance to bleomycin, 5-fluorouracil, and carboplatin. It has a slight collateral sensitivity to 1-dehydrotestosterone and lidocaine. H69AR has increased cell-cell adhesiveness compared to H69, but a similar growth rate in vitro and tumorigenicity in nude mice. When cultured in the absence of Adriamycin, there is a 40% decrease in resistance by 35 days of culture, compared to cells in continuous culture in drug, but no further decrease in resistance up to 181 days. Monoclonal antibodies to P-glycoprotein have no detectable reactivity with H69AR cells as determined by enzyme-linked immunosorbent assay and immunoblotting techniques. Thus, unlike most multidrug resistant cell lines, H69AR does not appear to express enhanced levels of P-glycoprotein. H69AR will provide a useful model for the study of multidrug resistance in human small cell lung cancer.

Topics: Animals; Antibodies, Monoclonal; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Small Cell; Cell Line; Colchicine; Daunorubicin; Doxorubicin; Drug Resistance; Enzyme-Linked Immunosorbent Assay; Epirubicin; Etoposide; Glycoproteins; Gramicidin; Humans; Immunosorbent Techniques; Isoxazoles; Lung Neoplasms; Menogaril; Mice; Mice, Inbred BALB C; Mitoxantrone; Nogalamycin; Phenotype; Vinblastine; Vincristine