Trabectedin is the first marine-derived anti-neoplastic drug approved for the treatment of advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for the treatment of patients with relapsed platinum-sensitive ovarian cancer. From the beginning of its development, trabectedin showed some peculiar properties that clearly distinguished it from other anti-cancer drugs. In this mini-review, we will outline the current state of knowledge regarding the mode of action of trabectedin, which appears to represent a new class of anti-neoplastic drugs acting both on cancer cells and on the tumour microenvironment.

BackgroundThe long term outcome of advanced sarcoma patients treated with trabectedin outside of clinical trials and the utility of maintenance treatment has not been reported.MethodsBetween 2003 and 2008, patients with advanced sarcoma failing doxorubicin could be treated within a compassionate use program (ATU, Temporary Use Authorization) of trabectedin in France using the standard 3-weekly regimen. Data from 181 patients (55%) were collected from 11 centres and analyzed.ResultsTrabectedin was given in first, second, third or fourth line in metastatic phase in 6%, 37%, 33% and 23% of patients respectively. With a median follow-up of 6 years, median PFS and OS were 3.6 months and 16.1 months respectively. The median number of cycles was 3 (range 1–19). Best response were partial response (PR, n = 18, 10%), stable disease (SD, n = 69, 39%) and progressive disease (PD, n = 83, 46%), non evaluable (NE, n = 9, 5%). Thirty patients (17%) had to be hospitalized for treatment- related side effects. Independent prognostic factors in multivariate analysis (Cox model) were myxoid LPS and line of trabectedin for PFS, and myxoid LPS and retroperitoneal sarcomas for OS. Patients in PR or SD after 6 cycles continuing treatment had a better PFS (median 5.3 vs 10.5 months, p = 0.001) and OS (median 13.9 vs 33.4 months, p = 0.009) as compared to patients who stopped after 6 cycles.ConclusionsIn this compassionate use program, trabectedin yielded similar or better PFS and OS than in clinical trials. Maintenance treatment beyond 6 cycles was associated with an improved survival.

Background:In order to investigate the mechanisms of acquired resistance to trabectedin, trabectedin-resistant human myxoid liposarcoma (402-91/T) and ovarian carcinoma (A2780/T) cell lines were derived and characterised in vitro and in vivo.Methods:Resistant cell lines were obtained by repeated exposures to trabectedin. Characterisation was performed by evaluating drug sensitivity, cell cycle perturbations, DNA damage and DNA repair protein expression. In vivo experiments were performed on A2780 and A2780/T xenografts.Results:402-91/T and A2780/T cells were six-fold resistant to trabectedin compared with parental cells. Resistant cells were found to be hypersensitive to UV light and did not express specific proteins involved in the nucleotide excision repair (NER) pathway: XPF and ERCC1 in 402-91/T and XPG in A2780/T. NER deficiency in trabectedin-resistant cells was associated with the absence of a G2/M arrest induced by trabectedin and with enhanced sensitivity (two-fold) to platinum drugs. In A2780/T, this collateral sensitivity, confirmed in vivo, was associated with an increased formation of DNA interstrand crosslinks.Conclusions:Our finding that resistance to trabectedin is associated with the loss of NER function, with a consequent increased sensitivity to platinum drugs, provides the rational for sequential use of these drugs in patients who have acquired resistance to trabectedin.

Nonadherent (NA), low density (LD), wheat germ agglutinin-positive (WGA+) murine hemopoietic stem cell-enriched preparations (HSCPs) were tested for the capability to reconstitute lymphohemopoietic elements in lethally irradiated mice. HSCPs from BALB/c mice reconstituted lethally irradiated, major histocompatiblity complex (MHC)-matched DBA/2 mice to normal histology of the thymus and spleen and normal humoral and cellular immune functions. By contrast, lethally irradiated B6 mice could not be reconstituted after transplantation with NA, LD, WGA+ cells from MHCmismatched BALB/c mice. We previously observed frequent survival, stable chimerism, and normally vigorous functioning immune systems in B6 mice transplanted with T-cell-depleted bone marrow from both BALB/c and B6 donors. To extend these findings to a stem cell transplantation system, lethally irradiated B6 mice were transplanted with NA, LD, WGA+ cells from both BALB/c and B6 mice. These mixed stem cell-enriched preparations did not reconstitute the lethally irradiated, MHC-mismatched mice. By contrast, such HSCPs from BALB/c plus DBA/2 into DBA/2 mice reconstituted the hematologic and lymphoid tissues and functional immune systems when the donor and the recipient pairs were matched at MHC and mismatched at multiminor histocompatibility barriers. These purified blood progenitors thus appear to lack certain cells/factors essential for engraftment and reconstituting recipients in a fully allogeneic environment.

The purpose of this cooperative study was to evaluate the quantity and quality of Ph1-negative progenitor cells mobilized in the peripheral blood of patients with chronic myelogenous leukaemia soon after aplasia induced by chemotherapy. 32 patients ineligible for allografting who were cytogenetically refractory to interferon-alpha (IFN-alpha) were entered into this study. The chronic phase varied widely, with a median duration of 17 months (range 3-90 months). All patients were treated with intensive conventional chemotherapy regimens and recombinant human granulocyte colony-stimulating factor (rhuG-CSF, lenograstim). Peripheral blood progenitor cells (PBPC) were harvested by leukaphereses during early recovery from chemotherapy-induced aplasia. A total of 119 leukaphereses were performed. Median numbers of CD34+ cells and CFU-GM collected were 2.04 x 10(6)/kg and 2 9 x 10(4)/kg, respectively. There was a significant correlation between white cell count and number of CD34+ cells in the leukaphereses (P = 0.0001, r2 = 0.41, n = 104). A strict correlation between the number of CD34+ cells and CFU-GM in the leukapheretic product (P = 0.0001, r2 = 0.39, n = 110) was observed. 21% of evaluable patients (6/29) achieved a complete cytogenetic remission in the leukapheretic product and the other four patients achieved a major cytogenetic response for an overall response of 35% (10/22 patients). To date, 16 patients have been autografted and are alive. Five of them are Ph1-negative (three patients) or partially Ph1-negative (two patients). In conclusion, despite the high-risk characteristics of this study population, Ph1-negative PBPC were successfully mobilized in more than one-quarter of patients using a chemotherapy plus rhuG-CSF regimen. The importance of this achievement is increased by the current lack of other practical methods of rescuing Ph-negative cells in such patients.