In vitro Sensitivity of Kaposi's Sarcoma Cells to Various Chemotherapeutic Agents Including Acyclic Nucleoside Phosphonates
Thierry Simonart, Graciela Andrei, Dominique Parent, Jean-Paul Van Vooren, Erik De Clercq, Robert Snoeck
1999
Antiviral Chemistry & Chemotherapy
Kaposi's sarcoma (KS) is an angioproliferative disease that has aroused considerable interest, because it is one of the major neoplasms found in patients with AIDS. Until the AIDS epidemic, this tumour was identified in three different settings: classic KS, a slowly growing tumour particularly prevalent among elderly men of Mediterranean or Jewish ancestry; African-endemic KS and immunosuppressive drug-related KS. All forms of KS show the same histology characterized by prominent angiogenesis
more »
... d by the proliferation of spindle-shaped cells, which are considered to be the tumour cells of KS. The current hypothesis to explain the formation and development of KS lesions is a multi-step pathway involving cytokine dysregulation, escape from programmed cell death (apoptosis) and active infection by human immunodeficiency virus type 1 (HIV-1) and/or by human herpesvirus 8 (HHV-8) (Ensoli et al., 1989 (Ensoli et al., , 1994 Chang et al., 1994; Noel et al., 1996; Mori et al., 1996; Simonart et al., 1998a) . The role of HHV-8 in this complex network is strengthened by cumulative bio-molecular studies indicating that HHV-8 contains transforming genes (for example, the open reading frame K12) (Muralidhar et al., 1998) . Current therapeutic options for patients with KS are mainly palliative and include radiotherapy, treatment with interferon-α and systemic chemotherapy. The probable involvement of a viral agent in the pathogenesis of the disease points to antiviral agents as possible therapeutic and/or prophylactic options in the management of the disease. In the present study, we investigated the effect of a wide panel of antiviral drugs on KS cells. We focused on acyclic nucleoside phosphonate (ANP) analogues, which have a broad spectrum antiviral activity against retroviruses and DNA viruses (Hitchcock et al.. The sensitivity to anticancer agents currently used in KS was studied in parallel. Human dermal microvascular endothelial cells (HDMEC), which are the probable vascular The involvement of a viral agent in the pathogenesis of Kaposi's sarcoma (KS) points to antiviral agents as possible therapeutic and/or prophylactic options in the management of the disease. In the present study we investigated the antiproliferative effects of various chemotherapeutic agents, including acyclic nucleoside phosphonates, on the growth of KS-derived cells. Nested PCR amplification demonstrated that these cells do not contain human herpesvirus 8 (HHV-8) DNA sequences. The cytotoxicity of the chemotherapeutic compounds was less pronounced in KS cells than in human dermal microvascular endothelial cells, which are considered to be the normal counterpart of KS cells. Stimulation of KS cells with basic fibroblast growth factor (bFGF) and correction of the IC 50 values by the doubling times revealed that the apparent chemotherapeutic resistance of KS cells could mainly be attributed to the long doubling times of these cells. bFGF-stimulated KS cells still exhibited no particular sensitivity to the acyclic nucleoside phosphonates whose activity extends to HHV-8, which is consistent with the absence of linear HHV-8 DNA synthesis in these cells. Our data suggest that neither anti-cancer agents nor antiviral agents such as the acyclic nucleoside phosphonates can discriminate efficiently between KS cells and normal endothelial cells.
doi:10.1177/095632029901000304
pmid:10431612
fatcat:bgt2yibfnbhwfmuji25oigmy64