melphalan and Uterine-Cervical-Neoplasms

Topics: Carcinoma; Chlorambucil; Cyclophosphamide; Female; Genital Neoplasms, Female; Humans; Hysterectomy; Lymph Node Excision; Melphalan; Ovarian Neoplasms; Progestins; Radiotherapy, High-Energy; Thiotepa; Uterine Cervical Neoplasms; Uterine Neoplasms

Topics: Antineoplastic Agents; Azaguanine; Aziridines; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Female; Fluorouracil; Humans; Infusions, Parenteral; Melphalan; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Triaziquone; Uracil Mustard; Uterine Cervical Neoplasms; Vinblastine

Radiotherapy has been standard therapy for locally advanced squamous cell cervical cancer. Neoadjuvant chemotherapy is being studied to improve responses and survival. We report a phase II study in locally advanced squamous cell cervical cancer (FIGO stages III and IVA) using chemotherapy with bleomycin, methotrexate and cisplatin (BMP) followed by radical radiotherapy. Of the 35 patients, 31 in stage III and 4 in stage IVA, 3 complete responses (CR) and 22 partial responses (PR) were achieved after chemotherapy treatment. Thirty-one patients completed radiotherapy; 19 achieved CR and 4 PR. Five-year actuarial survival for the entire group was 45% (95% confidence interval, 37-53%) with a median survival of 56 months. Patients with CR had a significantly better survival: the 5-year actuarial survival was 74% (95% CI, 59-89%). Recurrence developed in 4 of 19 patients. The most frequent side-effects were nausea and vomiting. Myelosuppression and impaired renal function also occurred. There was no evidence of radiotherapy toxicity enhancement. The stage and Karnofsky index were significant prognostic factors. It is concluded that BMP chemotherapy in advanced cervical cancer is effective and, followed by radiotherapy, allows a good control of this tumor. The group of patients with complete response have a low rate of recurrences and a long survival chance.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Carmustine; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Melphalan; Middle Aged; Prednisone; Survival Rate; Uterine Cervical Neoplasms

A major clinical problem regarding antitumoral treatment with DNA cross-linking agents such as cisplatin (Cisp), mechlorethamine (HN2) or its derivative melphalan (MLP) is intrinsic or acquired resistance to therapy, which frequently results from a resistance to apoptosis induction. In this study, aimed to identify novel sensitizing targets to DNA cross-linker-induced cell death, we demonstrated that MLP, Cisp and HN2 induce mitochondrial permeability transition pore (PTP)-mediated apoptosis in cervical and colon carcinoma cells. This apoptotic pathway is characterized by dissipation of the mitochondrial membrane potential, production of ROS, mitochondrial translocation of Bax, release of apoptogenic factors, caspase activation and nuclear alterations. The opening of PTP and subsequent apoptosis was reduced in Bax deficient cells and in cells with elevated Bcl-2 level, but not in cells invalidated for Bak. We further showed that, among the pro-apoptotic PTP regulators tested (VDAC1, creatine kinase, ANT1 and ANT3), exogenous overexpression of VDAC1 was the most effective in enhancing Cisp- and MLP-induced apoptosis. In addition, pharmacologically induced up-regulation of VDAC1 by the chemotherapeutic agent arsenic trioxide (As(2)O(3)) greatly sensitized HeLa cells to Cisp and MLP treatment. These data indicate that increased expression of VDAC1 appears as a promising strategy to improve DNA cross-linker-induced chemotherapy.

Topics: Antineoplastic Agents; Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; Cell Line, Tumor; Cisplatin; Colonic Neoplasms; Cross-Linking Reagents; DNA; Female; HeLa Cells; Humans; Mechlorethamine; Melphalan; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Proto-Oncogene Proteins c-bcl-2; Uterine Cervical Neoplasms; Voltage-Dependent Anion Channel 1

The objectives of the present study were to circumvent the moisture-associated instability, enhance bioavailability and achieve enhanced passive targeting of melphalan to the ovaries. Solubility of the drug was determined in various excipients to select the components of nanoemulsion. Pseudoternary phase diagrams were constructed using aqueous titration method. Formulations selected from the pseudoternary phase diagram were subjected to thermodynamic stability and dispersibility studies to select the final test formulations which were characterized for average globule size, polydispersity index (PDI), zeta potential, viscosity, refractive index, in-vitro drug release and percentage transmittance to optimize the final formulation. Pharmacokinetic and biodistribution studies of the optimized formulation in comparison to the pure drug suspension were done using γ-scintigraphy on female Balb/c mice. In-vitro cytotoxicity study on Hela cervical cancer cell lines was also done to compare the anticancer activity of the developed formulation with respect to the pure drug solution. In vitro-in vivo correlation was established for the amount of drug released and the amount of drug absorbed using suitable deconvolution. Stability studies on the final formulation were performed at 40 ± 2 °C and 75 ± 5% RH for 3 months and the shelf life was determined. Capmul MCM, Tween 80 and Transcutol P (S(mix)) were selected as the oil, surfactant and co-surfactant respectively on the basis of solubility studies. Out of 17 formulations prepared, six formulations were selected as the final test formulations on the basis of thermodynamic stress and dispersibility tests. The optimized formulation composed of oil (10%, v/v), S(mix) (35%, v/v), and double distilled water (55%, v/v). Bioavailability studies revealed 4.83 folds enhancement in bioavailability of the drug from nanoemulsion as compared to that from suspension. Biodistribution studies revealed more than 2 folds increase in uptake of the drug from nanoemulsion by ovaries as compared to that from the suspension. In vitro cytotoxicity studies demonstrated augmented anticancer potential of the drug in the form of nanoemulsion formulation in comparison to the drug solution. Level A correlation was established between the amount of drug released and the amount of drug absorbed. The shelf life of the formulation was found to be 1.30 years. The results demonstrate surface modified nanoemulsion to be a promising approach so as to in

Topics: Administration, Oral; Animals; Antineoplastic Agents, Alkylating; Biological Availability; Cell Death; Cell Proliferation; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Drug Stability; Emulsions; Excipients; Female; HeLa Cells; Humans; Inhibitory Concentration 50; Melphalan; Mice; Mice, Inbred BALB C; Nanoparticles; Nanotechnology; Particle Size; Solubility; Surface Properties; Surface-Active Agents; Technology, Pharmaceutical; Tissue Distribution; Uterine Cervical Neoplasms; Viscosity

Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for cancer therapy. In search of new compounds with strong antiproliferative activity and simple molecular structure, a new series of 2-amino-3-(3',4',5'-trimethoxybenzoyl)-5-(hetero)aryl ethynyl thiophene derivatives was prepared by the Sonogashira coupling reaction of the corresponding 5-bromothiophenes with several (hetero)aryl acetylenes. When these compounds were analyzed in vitro for their inhibition of cell proliferation, the 2- and 3-thiophenyl acetylene derivatives were the most powerful compounds, both of which exerted cytostatic effects at submicromolar concentrations. In contrast, the presence of a more flexible ethyl chain between the (hetero)aryl and the 5-position of the thiophene ring resulted in significant reduction in activity relative to the 5-(hetero)aryl acetylene substituted derivatives. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. We found that the antiproliferative effects of the most active compounds were associated with increase of the proportion of cells in the G(2)/M and sub-G(1) phases of the cell cycle.

Topics: Animals; Antimitotic Agents; Cell Line, Tumor; Cell Proliferation; Female; Humans; Leukemia; Mice; Molecular Structure; Structure-Activity Relationship; Thiophenes; Uterine Cervical Neoplasms

The FAS receptor-ligand system plays a key role in regulating apoptotic cell death, and corruption of this signaling pathway has been shown to participate in tumor-immune escape and carcinogenesis. We have recently demonstrated (Sun, T., X. Miao, X. Zhang, W. Tan, P. Xiong, and D. Lin. 2004. J. Natl. Cancer Inst. 96:1030-1036; Zhang, X., X. Miao, T. Sun, W. Tan, S. Qu, P. Xiong, Y. Zhou, and D. Lin. 2005. J. Med. Genet. 42:479-484) that functional polymorphisms in FAS and FAS ligand (FASL) are associated with susceptibility to lung cancer and esophageal cancer; however, the mechanisms underlying this association have not been elucidated. We show that the FAS -1377G, FAS -670A, and FASL -844T variants are expressed more highly on ex vivo-stimulated T cells than the FAS -1377A, FAS -670G, and FASL -844C variants. Moreover, activation-induced cell death (AICD) of T cells carrying the FASL -844C allele was increased. We also found a threefold increased risk of cervical cancer among subjects with the FASL -844CC genotype compared with those with the -844TT genotype in a case-control study in Chinese women. Together, these observations suggest that genetic polymorphisms in the FAS-FASL pathway confer host susceptibility to cervical cancers, which might be caused by immune escape of tumor cells because of enhanced AICD of tumor-specific T cells.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Cell Death; China; Cyclophosphamide; Fas Ligand Protein; Female; Flow Cytometry; Genetic Predisposition to Disease; Genotype; Haplotypes; HeLa Cells; Humans; Interleukin-2; Leukocytes, Mononuclear; Linkage Disequilibrium; Melphalan; Membrane Glycoproteins; Middle Aged; Polymorphism, Genetic; Risk Factors; Semustine; T-Lymphocytes; Tumor Necrosis Factors; Uterine Cervical Neoplasms

Topics: Aged; Antineoplastic Agents; Chromosome Deletion; Chromosomes, Human, Pair 7; Female; Humans; Male; Melphalan; Middle Aged; Monosomy; Multiple Myeloma; Myelodysplastic Syndromes; Uterine Cervical Neoplasms

Topics: Adenocarcinoma; Amino Acids; Animals; Antineoplastic Agents; Copper; Drug Therapy, Combination; Female; Intestinal Neoplasms; Lung Neoplasms; Mammary Neoplasms, Experimental; Melphalan; Mice; Neoplasms, Experimental; Rumen; Sarcoma 37; Uterine Cervical Neoplasms

Topics: Adult; Cervix Uteri; Female; Fluorouracil; Humans; Imidazoles; Melanoma; Melphalan; Neoplasm Metastasis; Prognosis; Uterine Cervical Neoplasms

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Thiotepa; Uterine Cervical Neoplasms

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Cyclophosphamide; Female; Fluorouracil; Humans; Hydroxyurea; Mechlorethamine; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Progestins; Thiotepa; Urea; Uterine Cervical Neoplasms

Topics: Abdomen; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Cyclophosphamide; Female; Geriatrics; Hodgkin Disease; Humans; Hypothermia; Hypothermia, Induced; Leiomyosarcoma; Mechlorethamine; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Pelvis; Rectal Neoplasms; Retroperitoneal Neoplasms; Uterine Cervical Neoplasms; Vaginal Neoplasms

Topics: Alkylating Agents; Antineoplastic Agents; Biomedical Research; Blood Platelets; Bone Marrow; Erythrocyte Count; Female; Humans; Leukocyte Count; Melphalan; Ovarian Neoplasms; Pharmacology; Tetracycline; Toxicology; Uterine Cervical Neoplasms