[Proapoptotic therapy with oblimersen (bcl-2 antisense oligonucleotide)--review of preclinical and clinical results]. / Proapoptotische Therapie mit Oblimersen (bcl-2-Antisense-Oligonukleotid)--Ubersicht über präklinische und klinische Daten.

The regulation of apoptosis is an important potential target for anticancer therapy. The mitochondrial Bcl-2 protein inhibits apoptosis and is therefore an important mediator of resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy and monoclonal antibody therapy. Oblimersen (Genasense, Aventis Pharmaceuticals / Genta Inc) is a 18mer antisense-oligonucleotide (ASO), which specifically binds to the first 6 codons of the human bcl-2 mRNA, resulting in degradation and destruction of the mRNA by RNAse H. Subsequently there is a significant decrease of bcl-2 translation. A growing number of preclinical and clinical studies suggests that the combination of cytotoxic therapy with Oblimersen results in synergistic anticancer efficacy in many hematologic and solid tumors. Due to its low toxicity profile, oblimersen is an ideal combination partner with conventional chemotherapy. Three randomized phase-III trials (malignant melanoma, chronic lymphocytic leukemia, multiple myeloma) have recently finished recruitment. The results of these studies will be available by the end of 2003. Based on preclinical data, a lot of nonrandomized phase-II studies on several different tumor types like AML, CML, NHL, prostate cancer and breast cancer are underway. The manipulation of proapoptotic and antiapoptotic factors in favor of proapoptotic factors by inhibition of the bcl-2 protein translation in order to enhance the efficacy of anticancer treatments represents a promising new treatment concept in oncology.

Where do we stand with 5-fluorouracil?

For nearly four decades, 5-fluorouracil (5-FU) has been the mainstay of treatment for colorectal cancer. Due to the lack of other agents with significant activity, tremendous efforts have been undertaken to increase the efficacy of 5-FU by investigating alternative schedules of delivery and biomodulation. However, bolus 5-FU in combination with folinic acid (FA), either as the Mayo Clinic or Roswell Park protocol, still represents the standard treatment for adjuvant and first-line palliative chemotherapy of colorectal cancer. In a recent meta-analysis, infusional protocols of 5-FU demonstrated increased response rates (14% to 22%) and a marginal, but significant survival benefit of 3 weeks (11.3 to 12.1 months). In view of the much higher costs and complicated management of infusional 5-FU regimens, this marginal survival benefit does not yet allow protracted 5-FU application to be defined as standard therapy. However, protracted 5-FU infusion in combination with radiation can be considered standard therapy as adjuvant treatment of rectal cancer, since it has demonstrated a significant increase in survival. In the future, oral 5-FU prodrugs may be substituted for infusional 5-FU. Furthermore, current data indicate that 5-FU will also be an essential component of combination chemotherapy protocols with the new active agents oxaliplatin, irinotecan, and raltitrexed. Preclinical studies show synergistic antitumor activity of 5-FU with these agents, which corresponds well with clinical response rates of 50% in untreated and 15% to 25% in 5-FU-refractory patients. Moreover, 5-FU-based pro-drug-active drug systems serve as excellent models for tumor-targeted gene therapy.

[Diagnostic and therapeutic management of the superior vena cava syndrome]. / Diagnostisches und therapeutisches Management der oberen Einflussstauung.

BACKGROUND: Superior vena cava syndrome (SVCS) is the clinical expression of obstruction of blood flow through the superior caval vein. In more than 80% of patients this complication is due to a malignant tumor, and in 60% of cases the first symptom of this tumor. DIAGNOSIS AND TREATMENT: If the clinical course of SVCS represents an absolute emergency, irradiation may have to be started immediately, even before the histologic diagnosis is established. Alternatively, expandable metallic stents have been used with considerable success for treatment of vena caval obstruction since patients respond immediately after stent implantation. For diagnosis, a chest X-ray and a CT scan should be performed. Chemotherapy is the treatment of choice for high-grade lymphomas, germ cell tumors and small-cell lung cancer since this modality is more effective than radiotherapy (response rate: 80%). For less chemotherapy responsive tumors radiotherapy is the primary treatment. Successful experience with thrombolytic agents is limited to treatment of catheter-induced SVCS, in contrast, only 20% of patients respond to thrombolytic therapy in the absence of a central catheter. Surgical resection of SVCS associated tumors has not improved survival rates and should be avoided.