ABSTRACT
We as well as others have recently shown that Hsp90 is overexpressed in multiple myeloma (MM) and critically contributes to tumour cell survival. Pharmacologic blockade of Hsp90 has consistently been found to induce MM cell death. However, most data have been obtained with MM cell lines whereas knowledge about the molecular effects of pharmacologic Hsp90 blockade in primary tumour cells is limited. Furthermore, these investigations have so far focused on geldanamycin derivatives. We analysed the biochemical effects of a novel diarylisoxazole-based Hsp90 inhibitor (NVP-AUY922) on signalling pathways and cell death in a large set of primary MM tumour samples and in MM cell lines. Treated cells displayed the molecular signature and pharmacodynamic properties for abrogation of Hsp90 function, such as downregulation of multiple survival pathways and strong upregulation of Hsp70. NVP-AUY922 treatment efficiently induced MM cell apoptosis and revealed both sensitive and resistant subgroups. Sensitivity was not correlated with TP53 mutation or Hsp70 induction levels and stromal cells from the bone marrow microenvironment were unable to abrogate NVP-AUY922-induced apoptosis of MM cells. Thus, NVP-AUY922 may be a promising drug for treatment of MM and clinical studies are warranted.
Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , Isoxazoles/pharmacology , Multiple Myeloma/drug therapy , Resorcinols/pharmacology , Signal Transduction , Apoptosis , Cell Line, Tumor , Coculture Techniques , Humans , Isoxazoles/therapeutic use , Multiple Myeloma/pathology , Resorcinols/therapeutic useABSTRACT
The effects of salm-calcitonin on breast cancer osteolytic skeletal metastases have been studied on conventional radiographs. Radiographic criteria for positive response have been defined. It is concluded that radiographs are inadequate for assessing the effects of salm-calcitonin.
Subject(s)
Bone Neoplasms/diagnostic imaging , Bone Neoplasms/drug therapy , Breast Neoplasms/pathology , Calcitonin/therapeutic use , Osteolysis/drug therapy , Bone Neoplasms/complications , Bone Neoplasms/secondary , Double-Blind Method , Female , Humans , Osteolysis/etiology , RadiographyABSTRACT
Between 1982 and 1987 we carried out a prospective randomized study to compare the effectiveness of high-dose half-body irradiation (HBI) (A), intensive combined chemotherapy (B), and local or locoregional radiotherapy (C) in the therapy of extended small cell lung carcinoma (SCLC). 99 patients with a histologically proved SCLC were assigned to the three therapeutic groups of series: A = 31 patients, B = 37 patients, C = 31 patients. The median survival period showed a statistically significant advantage (p less than 0.01) for the chemotherapy group (B = 46 weeks) versus the two radiotherapy groups (A = 19 weeks, C = 23 weeks). The survival after half a year, one year, and two years also gave a clear advantage for the chemotherapy group. No difference was found between the radiotherapy groups A and C. The high-dose HBI gave no improvement of the sad therapeutic situation for the extended SCLC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Bronchogenic/therapy , Carcinoma, Small Cell/therapy , Lung Neoplasms/therapy , Radiotherapy/methods , Carcinoma, Bronchogenic/mortality , Carcinoma, Small Cell/mortality , Female , Humans , Lung Neoplasms/mortality , Male , Middle Aged , Randomized Controlled Trials as Topic , Survival RateABSTRACT
Between 1982 and 1987 a prospectively randomized trial of sequential hemibody irradiation (SHBI) (A), a non-cross-resistant chemotherapy drug combination (B) and local and/or locoregional radiotherapy (C) in small cell lung cancer (SCLC) was conducted. Previously untreated patients with extensive SCLC were randomized into three arms: A = 31 patients, B = 37, C = 31. In the chemotherapy combination, the following were used: etoposide, doxorubicin, methotrexate (VAM) and procarbacine, vincristine, cyclophosphamide, lomustine (POCC) and prophylactic cranial irradiation (30 Gy). The results show that the median survival was significantly (P less than 0.01) better in chemotherapy (44 weeks) compared with 17 and 20 weeks in arms A and C, respectively. One year and 2 year survival rates were better for the chemotherapy arm. No differences were found between groups A and C. In comparing the total hospitalization time expressed as a percentage of overall survival, an advantage for group B was shown. In conclusion, high dose SHBI cannot be recommended as a standard therapy for extensive SCLC.
