Toxicity assessment of intratumoral injection of the herpes simplex type I thymidine kinase gene delivered by retrovirus in patients with refractory cancer.
Introduction of the herpes simplex type I thymidine kinase (HSV-TK) gene into tumor tissue, followed by ganciclovir, initiates a phosphorylation cascade that induces formation of a toxic ganciclovir triphosphate. Animal trials suggest that this ganciclovir triphosphate has antitumor activity. Here we report application of the HSV-TK transfection approach using a retroviral construct. Sixteen patients (median age 61.5 years) with refractory carcinoma (13 melanoma, 1 breast cancer, 1 nonsmall-cell lung cancer, and 1 osteogenic sarcoma) received intratumoral injection of HSV-TK retroviral vector at escalating doses (0.2x10(7) cfu per injection x 5 daily doses) and we evaluated them for toxicity and activity. We observed grade III pain associated with cellulitis in one patient following injection. Analysis of blood samples drawn between 3 and 28 weeks from 14 patients for replication-competent retrovirus by PCR analysis of the amphotrophic envelope revealed no replication-competent retrovirus. We injected 21 lesions. We identified no tumor responses of the injected lesions. Of 13 patients with advanced melanoma, 6 survived over one year. Thus, injection of retroviral delivered HSV-TK in patients with refractory cancer was well-tolerated.
Singh
S
S
US Oncology, Dallas, Texas 75246, USA.
Cunningham
C
C
Buchanan
A
A
Jolly
D J
DJ
Nemunaitis
J
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use / Q000633:toxicity; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D007267:Injections; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms / Q000628:therapy*; D012190:Retroviridae / Q000235:genetics* / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir