oblimersen and Carcinoma--Merkel-Cell

Merkel cell carcinoma is an aggressive neuroendocrine tumor with a high incidence of local recurrence, regional nodal and distant metastasis, and a high mortality rate. It has been linked to a polyomavirus in addition to immune suppression. Traditionally, treatment options have been limited to surgery and radiation therapy. Better understanding of the molecular pathways of infection and carcinogenesis has provided potential molecular targets and potential immunotherapies which are discussed in this review.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Benzamides; Biomarkers; Carcinoma, Merkel Cell; CD56 Antigen; Electrochemotherapy; Hepatitis A Virus Cellular Receptor 2; Humans; Imatinib Mesylate; Immunotherapy; Immunotherapy, Adoptive; Indazoles; Inhibitor of Apoptosis Proteins; Interferons; Interleukin-12; Interleukin-2; Ipilimumab; Lymphatic Metastasis; Membrane Proteins; Merkel cell polyomavirus; Oligonucleotides, Antisense; Piperazines; Polyomavirus Infections; Prognosis; Programmed Cell Death 1 Receptor; Pyrimidines; Receptors, Somatomedin; Skin Neoplasms; Somatostatin; Sulfonamides; Survivin; Thionucleotides; TOR Serine-Threonine Kinases

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine malignancy of the skin. Preclinical studies have identified up-regulation of the critical antiapoptosis gene bcl-2 in MCC. We conducted a multicenter phase II trial of the novel bcl-2 antisense agent (G3139, Genasense) in patients with advanced MCC.. Twelve patients (9 men, 3 women) with histologically confirmed metastatic or regionally recurrent MCC were enrolled. Ten patients (83%) had received prior chemotherapy. Eight patients (67%) had Karnofsky performance status of 90 to 100. Patients received continuous IV infusion of G3139 (7 mg/kg/d) via central venous access in an outpatient setting for 14 days, followed by a 7-day rest period. Response was assessed at 6-week intervals. Patients were allowed to continue therapy until unacceptable toxicity or disease progression.. No objective responses were observed. The best response was stable disease in 3 patients and progressive disease in 9 patients. A median of 4 doses per patient (total 46 doses) was administered. Dose delays and/or reductions were required in 6 patients. One patient developed grade 4 lymphopenia. One patient developed grade 3 renal failure characterized by grade 3-elevated creatinine and grade 4 hyperkalemia. Other grade 3 events included cytopenia (n = 5), aspartate aminotransferase/alanine aminotranferease elevation (n = 3), hypophosphatemia (n = 2), and pain (n = 1). The most frequent grade 1 to 2 toxicities were elevated creatinine, ALT elevation, hypokalemia, lymphopenia, and fatigue.. Bcl-2 antisense therapy (G3139) was well tolerated among patients with advanced MCC. Although probable antitumor activity was documented in 1 patient, no objective responses per Response Evaluation Criteria in Solid Tumors criteria were observed.

Topics: Aged; Carcinoma, Merkel Cell; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Oligonucleotides, Antisense; Prognosis; Skin Neoplasms; Survival Rate; Thionucleotides

Merkel cell carcinoma was first described in 1972 by Toker and is an aggressive neuroendocrine skin tumor with a high metastatic potential. Merkel cell carcinoma is thought to derive from the neuroendocrine (Merkel) cells of the skin, although in contrast to fetal and especially adult Merkel cells, Merkel cell carcinomas express high levels of the Bcl-2 oncoprotein. Bcl-2 is capable of blocking programmed cell death and has been shown to play an important role in normal cell turnover, tumor biology, and chemoresistance. High Bcl-2 expression leading to prolonged survival of cells may therefore be of importance in the biological and clinical characteristics of Merkel cell carcinoma. In a SCID mouse xenotransplantation model for human Merkel cell carcinoma, we investigated the influence of the bcl-2 antisense oligonucleotide G3139 (Genta) on tumor growth in comparison with control oligonucleotides or cisplatin. Bcl-2 antisense treatment, targeting the first six codons of the bcl-2 mRNA, resulted in either a dramatic reduction of tumor growth or complete remission, whereas reverse sequence and two-base mismatch control oligonucleotides or cisplatin had no significant antitumor effects compared with saline-treated controls. Apoptosis was enhanced 2.4-fold in the bcl-2 antisense treated tumors compared with the saline-treated group, and no other treatment showed a comparable increase in apoptosis. Our findings suggest that bcl-2 antisense treatment may be a novel approach to improve treatment outcome of human Merkel cell carcinoma.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Merkel Cell; Cell Division; Combined Modality Therapy; Female; Humans; Mice; Mice, SCID; Models, Biological; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Thionucleotides; Transplantation, Heterologous