Long-term outcome after intensive therapy with etoposide, melphalan, total body irradiation and autotransplant for acute myeloid leukemia

Intensive therapy and autologous blood and marrow transplantation (ABMT) is an established post-remission treatment for acute myeloid leukemia (AML), although its exact role remains controversial and few data are available regarding longer-term outcomes. We examined the long-term outcome of patients with AML transplanted at a single center using uniform intensive therapy consisting of etoposide, melphalan and TBI. In all, 145 patients with AML underwent ABMT: 117 in first remission, 21 in second remission and seven beyond second remission. EFS and OS were significantly predicted by remission status (P

Histone-deacetylase inhibitors for the treatment of cancer

Histone deacetylase inhibitors (HDACi) are a promising new class of chemotherapeutic drug currently in early phase clinical trials. A large number of structurally diverse HDACi have been purified or synthesised that mostly inhibit the activity of all eleven class I and II HDACs. While these agents demonstrate many features required for anti-cancer activity such as low toxicity against normal cells and an ability to inhibit tumor cell growth and survival at nanomolar concentrations, their mechanisms of action are largely unknown. Initially, a model was proposed whereby HDACi-mediated transactivation of a specific gene or set of genes was responsible for the inhibition of cell cycle progression or induction of apoptosis. Given that HDACs can regulate the activity of a number of nonhistone proteins and that histone acetylation is important for events such as DNA replication and mitosis that do not directly involve gene transcription, it appears that the initial mechanistic model for HDACi may have been too simple. Herein, we provide an update on the transcription-dependent and - independent events that may be important for the anti-tumor activities of HDACi and discuss the use of these compounds in combination with other chemotherapeutic drugs.

Defining the chemotherapeutic targets of Histone Deacetylase inhibitors

The use of many conventional chemotherapeutic drugs is often severely restricted due to dose-limiting toxicities, as these drugs target the destruction of the proliferating fraction of cells, often with little specificity for tumor cells over proliferating normal body tissue. Many newer drugs attempt to overcome this shortcoming by targeting defective gene products or cellular mechanisms that are specific to the tumor, thereby minimizing the toxicity to normal tissue. Histone deacetylase inhibitors are an example of this type of tumor-directed drug, having significant toxicity for tumors but minimal effects on normal tissue. These drugs can affect the transcriptional program by modifying chromatin structure, but it is not yet clear whether specific transcriptional changes are directly responsible for their tumor-selective toxicity. Recent evidence suggests that transcriptional changes underlie their cytostatic activity, although this is not tumor-selective and affects all proliferating cells. Here we present evidence that supports an alternative mechanism for the tumor-selective cytotoxicity of histone deacetylase inhibitors. The target is still likely to be the chromatin histones, but rather than transcriptional changes due to modification of the transcriptionally active euchromatin, we propose that hyperacetylation and disruption of the transcriptionally inactive heterochromatin, particularly the centromeric heterochromatin, and the inability of tumor cells to cell cycle arrest in response to a specific checkpoint, underlies the tumor-selective cytotoxicity of these drugs.

Impaired Antigen Presentation and Effectiveness of Combined Active/Passive Immunotherapy for Epithelial Tumors

Background: Although immunization with tumor antigens can eliminate many transplantable tumors in animal models, immune effector mechanisms associated with successful immunotherapy of epithelial cancers remain undefined. Methods: Skin from transgenic mice expressing the cervical cancer-associated tumor antigen human papillornavirus type 16 (HPV16) E6 or E7 proteins from a keratin 14 promoter was grafted onto syngeneic, non-transgenic mice. Skin graft rejection was measured after active immunization with HPV16 E7 and adoptive transfer of antigen-specific T cells. Cytokine secretion of lymphocytes from mice receiving skin grafts and immunotherapy was detected by enzyme-linked immunosorbent assay, and HPV16 E7-specific memory CD8(+) T cells were detected by flow cytometry and ELISPOT. Results: Skin grafts containing HPV16 E6- or E7-expressing keratinocytes were not rejected spontaneously or following immunization with E7 protein and adjuvant. Adoptive transfer of E7-specific T-cell receptor transgenic CD8(+) T cells combined with immunization resulted in induction of antigen-specific interferon gamma-secreting CD8(+) T cells and rejection of HPV16 E7-expressing grafts. Specific memory CD8(+) T cells were generated by immunotherapy. However, a further HPV16 E7 graft was rejected from animals with memory T cells only after a second E7 immunization. Conclusions: Antigen-specific CD8(+) T cells can destroy epithelium expressing HPV16 E7 tumor antigen, but presentation of E7 antigen from skin is insufficient to reactivate memory CD8(+) T cells induced by immunotherapy. Thus, effective cancer immunotherapy in humans may need to invoke sufficient effector as well as memory T cells.