V. 
Protocol 
Protocol 
V.A. Background 
V.A.1. Malignant Mesothelioma: The Clinical Problem 
Malignant mesothelioma is a primary neoplasm of the mesothelial lining of the pleural (80%) or 
peritoneal cavity (20%). It has been linked conclusively to prior exposure to asbestos (Antman, 
1993). Although relatively rare, mesothelioma accounts for approximately 6000 deaths per year 
(similar to that caused by Hodgkin’s Disease). The incidence of mesothelioma is increasing at a rate 
of 13% per year in American men and even faster in other parts of the world where exposure to 
asbestos is not well regulated (Sentes, 1989). In addition, mesothelioma is beginning to occur more 
frequently in women and those with no history of asbestos exposure (see Pisani et al., 1988). 
The disease is usually staged using the Butchart staging system: Stage I: Confined to ipsilateral 
pleura and lung or to peritoneal cavity; Stage II: Involving chest wall, mediastinum, pericardium, 
or contralateral pleura; Stage III: Involving both thorax and abdomen or lymph nodes outside the 
chest or abdomen; Stage IV: Distant blood born metastasis. At the time of diagnosis, stage II disease 
is most common (50%), stages I (18%) and III (28%) are less frequent, and stage IV disease is 
very infrequent (4%) (Pisani et al., 1988). Thus, in most cases, mesothelioma is a diffuse disease 
at the time of diagnosis. The tumor grows in a locally invasive fashion, often invading thoracic 
structures such as chest wall, pericardium, myocardium, and great vessels. Distant, blood-borne, 
metastases occur very late in the disease (Rusch 1993). 
The median survival for patients with mesothelioma at the time of diagnosis is between 12 and 18 
months, although survival time for patients with this tumor is notoriously variable. Curability of 
this disease is extremely rate. Therapy for mesothelioma has included three modalities used 
individually or in combination: operation, irradiation, and chemotherapy. Unfortunately, to date, 
none of these modalities has proven effective (Rusch, 1993). Surgical resection allows the removal 
of gross tumor but cannot provide microscopically negative margins. The use of radiation is limited 
by the huge volume of the tumor and the intolerance to radiation of adjacent intrathoracic organs. 
Radiation therapy has only produced a few long term survivors. There are no truly effective 
chemotherapeutic agents with the best reported response rates (using combination chemotherapy) of 
20-30%. Optimal selection of chemotherapy agents and timing remain undefined. 
Because of these shortcomings, several clinical trials utilizing aggressive surgical approaches (i.e. 
extrapleural pneumonectomy) coupled with radiation treatment and pre- or post-operative 
chemotherapy have been attempted in high performance status patients. Perioperative morbidity 
and mortality was high and, disappointingly, resulted in increments in survival measured in months 
(Sugarbaker et al., 1993, Rusch, 1993, Antman, 1993). It is clear that a novel therapeutic 
approach is desperately needed in this disease. 
V.A. 2. Gene Therapy: Rationale 
A number of characteristics thus make pleural malignant mesothelioma an attractive target for gene 
therapy. First, as discussed above, no effective therapy currently exists. Second, the location in 
the potential space of the thoracic cavity makes the tumor uniquely accessible, facilitating directed 
administration of novel agents and subsequent analysis of treatment effects. A surgical "debulking" 
procedure to remove gross disease, followed by gene therapy to remove residual disease would thus 
be technically feasible. Third, local extension of disease, rather than the development of widespread 
hematogenous metastases, is responsible for the morbidity and mortality associated with this 
neoplasm. Incremental improvement in local control could conceivably lead to significant 
improvement in survival or palliation. 
V.A. 3. Gene Therapy: The Prodrug Approach using HS Wtk 
Culver et al. (1992) have reported success in treating localized brain tumors by injection of 
fibroblasts secreting retroviruses engineered to contain the herpes simplex thymidine kinase 
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Recombinant DNA Research, Volume 20 
