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Bulletin Du Cancer Jan 2000
Review
Topics: Adenocarcinoma; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Ovarian Neoplasms
PubMed: 10673633
DOI: No ID Found -
Cell Jul 2015Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a...
Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor intensive and mostly limited to elucidating high-affinity binding target proteins. We introduce a regulatory network-based approach that elucidates genome-wide MoA proteins based on the assessment of the global dysregulation of their molecular interactions following compound perturbation. Analysis of cellular perturbation profiles identified established MoA proteins for 70% of the tested compounds and elucidated novel proteins that were experimentally validated. Finally, unknown-MoA compound analysis revealed altretamine, an anticancer drug, as an inhibitor of glutathione peroxidase 4 lipid repair activity, which was experimentally confirmed, thus revealing unexpected similarity to the activity of sulfasalazine. This suggests that regulatory network analysis can provide valuable mechanistic insight into the elucidation of small-molecule MoA and compound similarity.
Topics: Algorithms; Antineoplastic Agents; Epistasis, Genetic; Genome-Wide Association Study; Molecular Targeted Therapy; Neoplasms; Small Molecule Libraries
PubMed: 26186195
DOI: 10.1016/j.cell.2015.05.056 -
Journal of the American Geriatrics... Oct 2008To examine the association between frailty status and change in cognitive function over time in older Mexican Americans.
OBJECTIVES
To examine the association between frailty status and change in cognitive function over time in older Mexican Americans.
DESIGN
Data used were from the Hispanic Established Population for the Epidemiological Study of the Elderly.
SETTING
Five southwestern states: Texas, New Mexico, Colorado, Arizona, and California.
PARTICIPANTS
One thousand three hundred seventy noninstitutionalized Mexican-American men and women aged 65 and older with a Mini-Mental State Examination (MMSE) score of 21 or higher at baseline (1995/96).
MEASUREMENTS
Frailty, defined as three or more of the following components: unintentional weight loss of more than 10 pounds, weakness (lowest 20% in grip strength), self-reported exhaustion, slow walking speed (lowest 20% in 16-foot walk time in seconds), and low physical activity level (lowest 20% on Physical Activity Scale for the Elderly score). Information about sociodemographic factors, MMSE score, medical conditions (stroke, heart attack, diabetes mellitus, arthritis, cancer, and hypertension), depressive symptoms, and visual impairment was obtained.
RESULTS
Of the 1,370 subjects, 684 (49.9%) were not frail, 626 (45.7%) were prefrail (1-2 components), and 60 (4.4%) were frail (>/=3 components) in 1995/96. Using general linear mixed models, it was found that frail subjects had greater cognitive decline over 10 years than not frail subjects (estimate=-0.67, standard error=0.13; P<.001). This association remained statistically significant after controlling for potential confounding factors.
CONCLUSION
Frail status in older Mexican Americans with MMSE scores of 21 or higher at baseline is an independent predictor of MMSE score decline over a 10-year period. Future research is needed to establish pathophysiological components that can clarify the relationship between frailty and cognitive decline.
Topics: Aged; Altretamine; Cognition Disorders; Comorbidity; Female; Frail Elderly; Geriatric Assessment; Hand Strength; Humans; Male; Mental Status Schedule; Mexican Americans; Motor Activity; Muscle Strength; Southwestern United States; Vision Disorders; Walking
PubMed: 18811611
DOI: 10.1111/j.1532-5415.2008.01947.x -
Journal of Korean Medical Science Aug 2009The aim of this study was to assess the efficacy of consolidation therapy with hexamethylmelamine (HMM) in patients with advanced epithelial ovarian cancer (EOC)....
The aim of this study was to assess the efficacy of consolidation therapy with hexamethylmelamine (HMM) in patients with advanced epithelial ovarian cancer (EOC). Patients treated at our hospital between January 1997 and November 2006 and in documented clinical complete response from advanced ovarian cancer following front-line platinum-based therapy were retrospectively analyzed. The patients treated with HMM were compared to the patients of matched counterpart without consolidation therapy. Of 102 patients enrolled, 49 were treated with HMM and 53 received no consolidation treatment. For patients with HMM and observed patients, the mean age were 54.6 and 55.6 yr; the distribution of stage was similar (P=0.977); the optimal surgery was performed in 36 (73.5%) and 44 (83%) (P=0.336); the recurrence rate were 27 (55.1%) and 33 (62.3%) (P=0.463); and the median progression-free survival were 38 months and 21 months for patients with HMM and observed patients (P=0.235). No treatment-related adverse events were reported during the follow-up period. Although this study failed to show the significant survival benefit of consolidation therapy with HMM in patients with advanced EOC, we consider that our study can contribute data to investigate the effectiveness of consolidation therapy in epithelial ovarian cancer.
Topics: Altretamine; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Middle Aged; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Retrospective Studies
PubMed: 19654952
DOI: 10.3346/jkms.2009.24.4.679 -
Annals of Oncology : Official Journal... 1990The concept of using either alternating or sequential combination chemotherapy with non-cross-resistant combinations was tested in a randomized trial including 301... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
The concept of using either alternating or sequential combination chemotherapy with non-cross-resistant combinations was tested in a randomized trial including 301 previously untreated patients with advanced epithelial ovarian carcinoma. The sequential schedule consisted of CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) followed by PH (cisplatin, hexamethylmelamine) in nonresponders, CAF- greater than PH (n = 157), and the alternating regimen consisted of CAF/PH (n = 144). With a median observation time of 54 months, no statistically significant differences were found between the pathologically complete response (PCR) rates of 17% and 16%, respectively, nor were there any statistical differences in median disease-free survival for PCR patients (CAF- greater than PH 34+ months and CAF/PH 26+ months), in overall survival (28 and 24 months, respectively), or in time to treatment failure (10 and 11 months). The overall estimated cure rate was 13%. An equal degree of myelosuppression was seen with the two regimens, whereas neuro- and nephrotoxicity were more pronounced when PH was given sequentially to CAF than with the alternating schedule. We conclude that the sequential and the alternated use of doxorubicin- and platinum-based regimens yield equivalent results and that other approaches should be investigated to improve treatment effects.
Topics: Adult; Aged; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Middle Aged; Ovarian Neoplasms; Survival Rate
PubMed: 2127690
DOI: 10.1093/oxfordjournals.annonc.a057691 -
The Oncologist Oct 2005The manuscript by Armstrong et al. in this issue of The Oncologist, reviewing the toxicity and efficacy of full-dose topotecan delivered as second-line therapy in...
The manuscript by Armstrong et al. in this issue of The Oncologist, reviewing the toxicity and efficacy of full-dose topotecan delivered as second-line therapy in individuals with small cell lung cancer or ovarian cancer, will likely serve as both the most comprehensive and the final review of this active agent delivered at the U.S. Food and Drug Administration-approved dosage and schedule. The review represents large, relative lyhomogeneous patient populations with prior platinum exposure and convincingly describes topotecan as an agent with activity that is comparable with those of all other approved drugs in this setting and a well-defined and relatively circumscribed set of toxicities. While the activity of topotecan in small cell carcinoma provides individuals with the hope for further palliation at the time of tumor recurrence, as discussed by Dr. Markman in this issue, the best use of this agent in the management of recurrent ovarian cancer is far from clear because, in part, of a growing list of approved active agents, most notably liposomal doxorubicin, gemcitabine, and weekly paclitaxel; a return to platinum; or a host of other agents such as vinorelbine, altretamine, irinotecan, docetaxel, etoposide, and others. The most pressing need is to accept that palliative therapies are designed to palliate and improve symptoms, and to move away from end points of radiologic and marker response to a focus on "clinical benefit" and clinically more meaningful end points.
Topics: Antineoplastic Agents; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Ovarian Neoplasms; Palliative Care; Topotecan
PubMed: 16249349
DOI: 10.1634/theoncologist.10-9-698 -
British Journal of Cancer Jan 1983PMM is a water-soluble alternative to HMM. PMM has been administered as an intravenous infusion to 17 patients in a Phase I clinical trial. The dose-limiting toxicities... (Clinical Trial)
Clinical Trial
PMM is a water-soluble alternative to HMM. PMM has been administered as an intravenous infusion to 17 patients in a Phase I clinical trial. The dose-limiting toxicities were nausea and vomiting which were observed in all patients at 500 mg m-2 and above. The dose was not escalated above 1300 mg m-2 where nausea and vomiting were severe, prolonged (greater than 24 h) and poorly controlled by anti-emetics. Haematological, hepatic and renal toxicities were not observed. Neurological toxicity was not observed at low doses (less than 500 mg/m2) but could not be determined at higher doses due to intensive anti-emetic therapy. Pharmacokinetic studies (100-500 mg m-2) indicated that PMM plasma levels are dose-dependent and that the PMM disposition-phase half-life is prolonged in patients with abnormal liver function. It is concluded that the severe toxicity of PMM will limit the clinical utility of this compound and hence Phase II trials are not recommended.
Topics: Adult; Aged; Altretamine; Antineoplastic Agents; Clinical Trials as Topic; Female; Humans; Kinetics; Liver; Liver Neoplasms; Male; Middle Aged; Nausea; Neoplasms; Nervous System Diseases; Triazines; Vomiting
PubMed: 6401427
DOI: 10.1038/bjc.1983.3 -
Japanese Journal of Cancer Research :... Aug 1995We have evaluated the antitumor activity of Altretamine (hexamethylmelamine, HMM) on human carcinoma xenografts serially transplanted in nude mice. Five human breast...
We have evaluated the antitumor activity of Altretamine (hexamethylmelamine, HMM) on human carcinoma xenografts serially transplanted in nude mice. Five human breast carcinoma xenografts, MX-1, T-61, MCF-7, R-27 and Br-10, were inoculated subcutaneously into female nude mice. Two human stomach carcinoma xenografts, SC-1-NU and St-4, and three human colon carcinoma xenografts, Co-3, Co-4 and Co-6, were inoculated subcutaneously into male nude mice. One pellet of 17 beta-estradiol (0.1 mg/mouse) was inoculated subcutaneously in the mice transplanted with MCF-7 when the tumors were inoculated. HMM was administered per os daily for 4 weeks. MX-1 and T-61 tumors regressed completely after treatment with HMM at a dose of 75 mg/kg (the maximum tolerated dose: MTD) for MX-1 and 25 mg/kg for T-61. Br-10 was sensitive, whereas MCF-7 and R-27 were resistant to HMM at its MTD. HMM exerted the most potent antitumor effect against T-61. Against MX-1, it exerted an antitumor effect equivalent to that of cisplatin or cyclophosphamide. In addition, this agent was effective against all stomach and colon carcinoma xenografts, in particular St-4 (T/C% = 10.7: the mean tumor weight of treated group/the mean tumor weight of control group) and Co-3 (T/C% = 31.5%) which are insensitive to presently available agents. HMM seems worthy of further clinical investigation as a candidate agent to treat breast, stomach, colon and other carcinomas.
Topics: Altretamine; Animals; Antineoplastic Agents, Alkylating; Breast Neoplasms; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Stomach Neoplasms; Transplantation, Heterologous
PubMed: 7559101
DOI: 10.1111/j.1349-7006.1995.tb02467.x -
British Journal of Cancer Jan 1991Forty-six patients with recurrent ovarian cancer were reoperated, and cancer samples for the subrenal capsule assay (SRCA) were collected from 23 of them, whereas this... (Clinical Trial)
Clinical Trial
Forty-six patients with recurrent ovarian cancer were reoperated, and cancer samples for the subrenal capsule assay (SRCA) were collected from 23 of them, whereas this test was not done in the remaining 23 control patients. The SRCA was evaluable in 22 cases (96%). Taken together, no significant difference appeared in the 3 years' survival figures between the groups: seven of 22 patients (32%) with the evaluable SRCA and six of 23 control patients (26%) were alive. However, a further analysis of the data revealed that the SRCA guided the selection of chemotherapy only in 15 patients, whereas tumour samples were resistant to all cytostatics tested in six cases and toxic side-effects limited the clinical application of the test results in the remaining one case. Four of the 11 patients (36%) whose further chemotherapy was strictly chosen based on the SRCA and seven of the 24 patients (29%) whose treatment was based on physician's choice survived at least 3 years. Our conclusion is that the SRCA is of limited value in the selection of second-line chemotherapy in recurrent ovarian cancer.
Topics: Adult; Aged; Altretamine; Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Cystadenocarcinoma; Doxorubicin; Drug Screening Assays, Antitumor; Epirubicin; Female; Follow-Up Studies; Humans; Melphalan; Mice; Middle Aged; Ovarian Neoplasms; Subrenal Capsule Assay
PubMed: 1899195
DOI: 10.1038/bjc.1991.17 -
British Journal of Cancer Sep 1990The data on 914 patients enrolled in four randomised trials in advanced ovarian cancer, consecutively conducted by the same cooperative group between 1978 and 1986, were...
The data on 914 patients enrolled in four randomised trials in advanced ovarian cancer, consecutively conducted by the same cooperative group between 1978 and 1986, were analysed with the aims of: (1) determining the impact of selected prognostic variables on survival; (2) finding, from the interaction of favourable prognostic factors and treatment, an approximate estimate of the magnitude of the survival advantage associated with the use of platinum-based combination chemotherapy. The overall 3-year survival in this series of patients is twice that reported historically (22%; 95% CL 18.7-25.4). The proportional hazard regression model was used to perform the analysis on survival. Residual tumour size, age, FIGO stage and cell type were all independent determinants of survival. Differences in survival from the various prognostic groups were impressive with 5-year survival rates ranging from 7 to 62%. However, these differences were not qualitative (i.e. the kinetics of survival were similar for the best and the worst groups) suggesting that current prognostic factors are of little use for selecting 'biologically' different sub-populations. Platinum-based regimens were associated to an overall prolonged median survival, but this benefit was not observable in the subgroup with most favourable prognosis (less than 2 cm residual tumour size). The implications of these observations for clinical research and ovarian cancer patients care are discussed.
Topics: Age Factors; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Ovarian Neoplasms; Prognosis; Regression Analysis; Survival Analysis
PubMed: 2119684
DOI: 10.1038/bjc.1990.315