acyclovir and Cell-Transformation--Neoplastic

Topics: Abnormalities, Drug-Induced; Acyclovir; Animals; Animals, Newborn; Antiviral Agents; Cell Transformation, Neoplastic; Eye; Female; Growth; Guanine; Immunity; Lethal Dose 50; Male; Mutagenicity Tests; Mutation; Neoplasms; Pregnancy; Reproduction; Skin; Wound Healing

The clinical, immunopathologic, and virologic features of the lymphoproliferative diseases occurring after renal transplantation have been characterized. Clinically, patients may present with an infectious mononucleosis-like illness or with localized solid tumor masses. These lymphoproliferative diseases have unique histologic features that can be classified as polymorphic diffuse B-cell hyperplasia (PDBH) or polymorphic B-cell lymphoma (PBL). Immunologic cell-typing studies have shown that the majority are polyclonal B-cell proliferations, but monoclonal B-cell tumors have also been documented. These B-cell proliferations may, however, evolve from a benign polyclonal B-cell hyperplasia to a monoclonal malignant lymphoma. The Epstein-Barr virus (EBV) has been implicated as the cause of these disorders. Serologic studies frequently demonstrate evidence of a primary or reactivation infection, touch imprints from involved tissue may stain for the presence of EBNA (Epstein-Barr nuclear antigen), and EBV DNA hybridization studies demonstrate the presence of EBV-specific DNA sequences within tumor cells. Since EBV induces a polyclonal B-cell proliferation in vitro and in vivo, the polyclonality of these diseases also implicates EBV. Acyclovir, a new synthetic antiviral agent that inhibits EBV DNA replication may be effective in some patients during the polyclonal growth phase but is ineffective once the tumor evolves into a monoclonal lymphoma. We have identified several factors that may be useful in predicting responsiveness to acyclovir therapy.

Topics: Acyclovir; Adult; Antigens, Viral, Tumor; B-Lymphocytes; Cell Transformation, Neoplastic; DNA; Herpesvirus 4, Human; Humans; Hyperplasia; Kidney Transplantation; Lymphoma; Lymphoproliferative Disorders; Nucleic Acid Hybridization; Transplantation Immunology

Rat embryo fibroblasts (REF) morphologically transformed by herpes simplex virus type 2 (HSV-2) and tumor-derived cells were tested for ability to grow in the presence of 9-(2-hydroxyethoxymethyl) guanine (acyclovir). Results indicated that the effective dose of acyclovir (ACV) required to inhibit HSV-2-transformed and tumor-derived cell growth by 50% (ED50) compared to mock-treated control cells averaged 15 to 75 micrograms/ml. In contrast, the ED50 of acyclovir was more than HEp-2 cells. HSV-2-transformed and tumor-derived cells after both low (less than 30) and high (greater than 30) serial passages expressed detectable levels of the virus-coded thymidine kinase (TK) measured in cell extracts by serum neutralization assay. HSV-2-transformed or tumor-derived cells converted two- to ten-fold more acyclovir to phosphorylated forms than nontransformed REF cells. Preliminary data showed that the drug inhibited tumor development in newborn syngeneic rats inoculated with HSV-2-transformed cells. The inhibitory activity of acyclovir and presence of low levels of HSV-2 TK activity appeared to correlate.

Topics: Acyclovir; Animals; Antineoplastic Agents; Cell Division; Cell Line; Cell Transformation, Neoplastic; Humans; Phosphorylation; Rats; Simplexvirus; Thymidine Kinase; Tumor Virus Infections

Mutants of HSV which are resistant to acyclovir (acycloguanosine) have been isolated following serial passages of several herpes simplex virus (HSV) strains in the presence of the drug. The majority of the mutants isolated are defective in induction of thymidine kinase (TK) and this is consistent with the observation that independently isolated TK- viruses are naturally resistant to ACV. One mutant is described (SC16 R9C2) which is resistant in biochemically transformed cells which express HSV TK. This suggests that its resistance resides at a level other than TK. It is also resistant to phosphonoacetic acid, suggesting that the DNA polymerase locus may be involved. A further mutant is described [Cl (101) P2C5] which induces normal levels of TK, although the nature of resistance of this virus is not yet elucidated.

Topics: Acyclovir; Animals; Cell Line; Cell Transformation, Neoplastic; Drug Resistance; Enzyme Induction; Guanine; Humans; Mutation; Phosphonoacetic Acid; Simplexvirus; Thymidine Kinase