ABSTRACT
MV-NIS is an oncolytic measles virus encoding the human thyroidal sodium iodide symporter (NIS). Here, we report the results of preclinical pharmacology and toxicology studies conducted in support of our clinical protocol "Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with or without Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma." Dose-response studies in the KAS-6/1 myeloma xenograft model demonstrated a minimum effective dose of 4 x 10(6) TCID50 (tissue culture infectious dose 50)/kg. Toxicity studies in measles-naive squirrel monkeys and measles-susceptible transgenic mice were negative at intravenous doses up to 10(8) and 4 x 10(8) TCID50/kg, respectively. Abundant viral mRNA, maximal on day 8, was detected in cheek swabs of squirrel monkeys, more so after pretreatment with cyclophosphamide. On the basis of these data, the safe starting dose of MV-NIS for our clinical protocol was set at 1-2 x 10(4) TCID50/kg (10(6) TCID50 per patient).
Subject(s)
Antineoplastic Agents/pharmacology , Cyclophosphamide/pharmacology , Measles virus , Multiple Myeloma/drug therapy , Oncolytic Virotherapy/methods , Oncolytic Viruses , Symporters/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents, Alkylating/pharmacology , Cell Line, Tumor , Cyclophosphamide/administration & dosage , Female , Humans , Injections, Intravenous , Measles virus/genetics , Measles virus/isolation & purification , Membrane Cofactor Protein/genetics , Mice , Mice, Inbred ICR , Mice, SCID , Mice, Transgenic , Oncolytic Virotherapy/adverse effects , RNA, Viral/isolation & purification , Reverse Transcriptase Polymerase Chain Reaction , Saimiri , Symporters/administration & dosage , Transplantation, HeterologousABSTRACT
A comparative study of the effects of ultraviolet radiation on three Bacillus subtilis phages is presented. Phages phi 29, SPP1 and SPO2c12 or their DNAs were irradiated by UVC (254 nm) and quantum yields for inactivation were calculated. For each phage, the purified DNA was found to be more sensitive than the intact virus when assayed in a uvr+ host. The data imply that this is because transfecting DNA is repaired less efficiently than DNA of the intact phage; rather than because of differences in sensitivity to lesion production. Even though phi 29 has the smallest target size of the three phages, phi 29 and its DNA are the most sensitive. Phages SPO2 and SPP1 code for gene products which complement the repair system of the host. The transfecting DNA of phage SPP1 is extremely sensitive to UV damage when assayed in a uvr-host. This is attributed to the fact that in transfection SPP1 DNA must undergo recombination for productive infection to occur. The recombination process strongly interferes with the repair of damaged DNA.
Subject(s)
Bacillus subtilis/genetics , Bacteriophages/radiation effects , DNA Damage , DNA Repair , DNA, Viral/radiation effects , Genes, Bacterial , Ultraviolet RaysABSTRACT
A new autosomal recessive gene in mice is described that produces deficiencies in central nervous system myelin and quaking or trembling of the hindquarters during locomotion. Although both behavioral and central nervous system abnormalities resembled those produced by qk, the new mutation was not an allele of qk. We propose that the new mutation should be labeled myelin deficient (symbol, mld).
