CHAPTER 28: IMMUNOTHERAPY AND GENE THERAPY FOR MESOTHELIOMA
keywords, immunotherapy, mesothelioma, gene therapy, interferon and mesothelioma, immune cells and mesothelioma, SV 40, mesothelioma vaccine.
28.0 RATIONALE FOR IMMUNOTHERAPY
Immunotherapy and gene therapy are important investigational drugs to fight mesothelioma.
The rationale for immunotherapy is the existence of immune abnormalities in patient with MPM. Moreover, some human mesothelioma cell lines are sensitive to cytokines like interferon -, -IFN, and interleukin 2, and to some immune cells, which suggests that immunointervention would be beneficial. Intrapleural administration of interleukin 2 has resulted in objective responses in 19 to 55% of the cases in two trials including low numbers of patients in the early stages of disease. Monnert (1)
28.1 INTERFERONS
28.11 What are Interferons
Interferons are proteins secreted by immune cells that "interfere" with a virus’s ability to reproduce and proliferate. Interferon has had some significant beneficial effect in treating mesothelioma though significant side effects have been associated generally with Interferon. In the laboratory, low concentrations of interferon help boost the power of natural killer T cells. With some tumors, interferons can help inhibit the development of the blood vessels that tumors need to metastasize and grow, a process called angiogenesis.
There are three main types and 17 subtypes of interferon.
28.12 Studies with Interferon and Mesothelioma
One study reported an impressive response rate for patients with stage 1 disease:
Eighty-nine patients were included over 46 months. Eight histologically confirmed complete responses and nine partial responses with at least a 50% reduction in tumor size were obtained. The overall response rate was 20%. Most responses were achieved in patients with early stage disease. The response rate for patients with Stage I disease was 45%. Tolerance of interferon was good. Treatment was performed on an outpatient basis. The main side effects were hyperthermia, liver toxicity, neutropenia, and catheter-related infection. CONCLUSIONS. Gamma-interferon is effective mainly in Stage I mesothelioma, especially if the tumor is confined to the parietal or diaphragmatic pleura (Stage IA). Boutin (4)
Unfortunately, the abstract does not report median survival figures. The favorable results for stage 1 can be interpreted as indicating the effectiveness of Interferon with this subgroup or that most therapies will be more successful on patients with limited disease.
28.13 Why Interferon Works
A recent study explains how Interleukin works on laboratory animals.
"Malignant mesothelioma appears to be sensitive to immunotherapeutic approaches, and one of the most powerful immunomodulatory cytokines with antitumor effects is interleukin (IL)-12. We have previously shown in a murine model of MM that systemic administration of recombinant IL-12 induces a potent anti-MM immune response. The nature and accessibility of MM tumors means that they are suitable candidates for direct cytokine and gene-transfer therapeutic approaches. In mixing experiments, paracrine IL-12 production inhibited growth of untransfected MM cells provided that cells producing IL-12 represented more than 50-80% of the inoculum.... This study shows that paracrine secretion of IL-12, generated by gene transfer, can induce immunity against MM that can act locally and also at a distant site. In addition, there was no evidence of toxicity, which has been associated with the systemic administration of IL-12, indicating that this cytokine is a good candidate for experimental gene therapy in MM. Caminschi (5)
However, A study at New York’s renowned Sloan Kettering reported,
"The combination of low-dose interferon alpha-2a and carboplatin did not result in greater antitumor activity than that reported for single-agent carboplatin in advanced malignant mesothelioma. Although toxicity was mild, carboplatin and low-dose interferon, given at this dose and schedule, cannot be recommended for this patient group." O’Reilly (6).
28.14 Complimentary Effects of Inferon and Chemotherapy
Perhaps the lesson is that low doses of Interferon are unlikely to effect
favorable results, and the dosage must be compared with the more favorable studies. Significant side effects have been reported with Interferon so defining the maximum tolerable dose is no easy. The median survival is somewhat higher than with other treatments as is the progression to more serious disease. Initially, the results of a 2002 study of interpleural administration of Interferon are modest. "Among the 14 evaluable patients, 2 patients (patients 4 and 11) had a partial response. The overall response rate of patients actually treated was 14%." Monnert (1). The author explains,
After completion of the cellular therapy, 10 patients were treated by chemotherapy as their diseases progressed." Two patients (patients 13 and 15) achieved a stabilization of their disease. The disease in patient 13 again progressed after 26 months, and this patient died at 45 months. Patient 15 was still alive in December 2000, with a follow-up of 47 months. The median survival of patients actually treated, including those who received chemotherapy after AM treatment was 29.2 months. At last follow-up (December 2000), 4 of the 17 patients were alive. Patient 4 had completed chemotherapy and had a very slow-progressing disease. The disease in patients 15 and 3 was progressive at 47+ and 41+ months, respectively; patient 1 was still disease-free at 69+ months.Monnert (1).
The median survival rate of 29.2 months and the results of several patients surviving at or close to four years is impressive. Yet the partial response rate of 14% is unimpressive. This indicates to me that the most potent impact of the Interferon was its later favorable impact upon chemotherapy for several patients. A Turkish study found moderately favorable results, a response rate of 24% combining Interferon with Cisplatin. Metintas (14)
"OBJECTIVE: To investigate the therapeutic activity and toxicity of combination chemoimmunotherapy with cisplatin, mitomycin, and interferon (IF)-alpha2a, by comparing the responses in a group of patients with diffuse malignant pleural mesothelioma (DMPM) to the responses in a control group of DMPM patients given supportive care alone.... Forty-three patients with DMPM received chemoimmunotherapy until the end of the survey; 19 patients were given supportive therapy alone after refusing chemoimmunotherapy. INTERVENTIONS: Drugs were administered according to the following schedule: IV cisplatin, 30 mg/m2 qd on days 1 and 2; IV mitomycin, 8 mg/m2 on day 1; and subcutaneous IFN-alpha2a, 4.5 million IU twice weekly.... A total of 10 objective responses (ORs) in 43 patients (23%) were assessed, including 2 complete responses (5%), 4 partial responses, and 4 regressions. Seventeen patients had stable disease, and 16 patients had progression. The median survival time was 11.5 months for the 43 patients who received chemoimmunotherapy and 7.0 months for the 19 patients who received supportive therapy alone. The difference in survival times between the chemoimmunotherapy and supportive therapy groups was not significant. However, the median survival time for the patients who had OR was 21.3 months, which is significantly longer than that of the patients who received supportive care alone and that of patients with progressive disease (6 months). The toxicities associated with the treatment schedule of this study were, for the most part, tolerable. CONCLUSIONS: The drug combination used in this study is moderately effective and well tolerated in patients with DMPM, especially in those who responded to the treatment."
28.16 Cellular Studies of Interferon and Chemotherapy
Some cell studies support the hypothesis that Interferon can improve the efficacy of chemotherapy. One study reported, " A combination of IF-alpha and IF-gamma consistently augmented the response of the cell lines to methotrexate, by as much as 75% for one cell line, although the response to the individual IFNs was variable. Hand (3)
28.2 INTERLEUKIN
28.21 Interleukin
A 1995 study of Interleukin reported modest results:
"Partial response (PR) occurred in 4 of 21 evaluable patients (19%; 95% confidence interval 5-42%) with a median time to progression of 12 months (range 5-37). Stable disease (SD) occurred in seven patients with a median time to progression of 5 months (range 2-7). There were no complete responses (CRs). The median overall survival was 15.6 months (range 3.0-43). No relationship between the dose of IL-2 and response rate was observed. We conclude that IL-2 given intrapleurally is accompanied with acceptable toxicity and has anti-tumour activity against mesothelioma
In a phase 1 study of 13 patients with mesothelioma, four patients had a partial response, and one a complete response. A phase 1 trial is designed to determine tolerable doses as well as assess response. Some anemia and renal or kidney problems were noted from the therapy, but overall the study showed promise with phase 2 trials expected. Porohit (10)In a French phase II study, over 50% of the participants showed some tumor reduction from Interleukin-2:
Several clinical studies have demonstrated objective antitumoral responses to intrapleural interleukin-2 (IL-2) administration in the treatment of malignant pleurisy..... Based on these results, a Phase II study was conducted, in which intrapleural IL-2 (21 x 10(6) IU/m2/day for 5 days) was given to patients with MPM. (malignant pleural mesothelioma) .... Twenty-two patients entered this study. Of the 22 cases of MPM, 19 were epithelial, 2 were mixed, and 1 was fibrosarcomatous. Three patients had Stage IA disease, 1 had Stage IB, 16 had Stage II, 1 had Stage III, and 1 had Stage IV (Butchart classification).... There were 11 partial responses and 1 complete response. Stable disease occurred in 3 patients and disease progression in 7 patients. The overall median survival time was 18 months; the median survival time of responders differed significantly from that of nonresponders (28 months vs. 8 months, P < 0.01). The 24- and 36-month survival rates for responders were 58% and 41%, respectively. CONCLUSIONS: These results confirm that intrapleural administration of IL-2 is well tolerated and has antitumor activity in patients with MPM. Astroul (7)
28.4 EPIDERMAL GROWTH FACTOR INHIBITORS AND MESOTHELIOMA
28.41 Overview
Given the limited success of surgery and chemotherapy, scientists are evaluating other forms of treatment for mesothelioma. The development and spread of cancers are prompted by growth factors, signals from one cell to another.
A prominent growth factor is the epidermal growth factor. The epidermal growth factor (EGF) is associated with the creation and spread of lung cancer as well as other types of cancer. Connecting with its receptor, EGFR, this sets in motion various carcinogenic events. Use of epidermal growth factor inhibitors have stabilized disease in some lung cancer patients, though the rates of complete cure or even partial response (reduction of tumor volume by one half) have been low. Since the EGFI’s do not affect all cells, but target a specific receptor, they have much fewer. The most common side effect is skin irritation since the epidermal growth factor is connected with skin (dermal) regeneration).
Rather than disrupting the immune system as with Interferon, or performing risky surgery, this treatment is minimally intrusive. Drugs which inhibit this growth factor are beginning to play an important role in treatment of patients with advanced non-small cell cancer, and may play an equal role in treating mesothelioma. Our chapter on EGF and Iressa discusses these drugs and recent studies, and here we look at such drugs specifically in relation to treatment for mesothelioma.
"Govindan and colleagues have investigated EGFR receptor expression in mesothelioma tissue, using ZymedTM antibodies. They found that nearly 60% of samples overexpressed EGFR, while none overexpressed HER-2, suggesting that it is worth considering anti-EGFR therapy in patients with mesothelioma. http://Www.EGFR(13 egfrinfo.com)
A recent presentation found that asbestos prompted production of the
epidermal growth factor and this could be duplicated in the laboratory:
"Over-expression of the epidermal growth factor receptor (EGFR) is a common finding in many solid tumors, including lung, breast and mesothelioma, and has been shown to correlate with both a poor prognosis and resistance to radiation and chemotherapy.... Recent evidence suggests that up-regulation and activation of EGFR may play a critical role in early carcinogenic events.... carcinogenic asbestos fibers upregulate the expression of the EGFR. Exposure of MET 5A cells to asbestos leads to the activation of nuclear factor-kB (NF-kB), a transcription factor important in the regulation of a number of genes intrinsic to inflammation, proliferation and lung defences. This study set out to examine the relationship between EGFR and NF-kB in MET 5A cells exposed to asbestos fibers... The selective EGFR tyrosine kinase inhibitor, PKI166 (Novartis), inhibited the DNA binding of NF-kB mediated by crocidolite asbestos fibers.... Modulation of the asbestos-mediated EGFR/NF-kB signaling pathway may be important in the development of novel therapeutic strategies for both the chemoprevention and treatment of malignant mesothelioma." Faux (4)
28.42 Mesothelioma Cell Studies
A recent cell study concludes "the EGFR mediates both asbestos-induced proto-oncogene expression and epithelial cell proliferation, providing a rationale for modification of its phosphorylation in preventive and therapeutic approaches to lung cancers and mesothelioma." Manning (15). Iressa is the most well-known EGFR.
28.43 Human Studies
Investigation is continuing with clinical trials, though I have not located published reports.
28.44 Iressa Use with Mesothlioma
Iressa is an FDA approved drug for non-small cell lung cancer. Since it is FDA approved, doctors can prescribe it for other uses, so-called off-label. While the drug has not been approved or found effective for mesothelioma, some patients could seek its use, particularly if other alternatives were not available for various reasons. A doctor would then have to determine whether the drug should used off-label.
28.5 COX-2 INHIBITORS AND MESOTHELIOMA
28.51 Overview
Cox-2 inhibitors have been shown to impact inflammatory processes without producing significant side effects. The production of cox-2 is associated with carcinogenic process and in cell studies, cox-2 inhibitors suppressed various carcinogenic processes.
Cox-2 inhibitors like Celebrex present an alternative. We know that drugs like Celebrex target and have the ability to impact Cox-2, they have limited side effects, and the limited side effects mean they can be used with other drugs. (18) (discussing possible used of cox-2 inhibitors with immunotherapy). Can cox-2 inhibitors work with mesothelioma.
28.52 Cox2's role in Mesothelioma
Cox-2 appears to play a role in the development and spread of mesothelioma. Edwards (17) "The data presented here demonstrate that cells in mesothelioma tissue, as opposed to normal mesothelial linings, express detectable levels of the inducible enzymes, NOS2 and COX2." Manning (16). "Human mesothelioma tumors have been shown to overexpress COX-2 and high levels of COX-2 protein have been demonstrated to be a prognostic factor, indicating poor outcome in this tumor."
28.53 Cell Studies of Cox-2 Inhibitors
A recent study looked at Celebrex and mesothelioma. "We determined that inhibition of COX-2 by oral administration of Rofecoxib significantly slowed but did not cure the growth of small tumors in mesothelioma-bearing mice." (Delong 19). The low side effects associated with Celebrex mean that this drug could fruitfully be combined with others.
and as an adjunct, tested them on mesothelioma. More money is needed for research and targeted testing of drugs for mesothelioma.
28.6 OTHER DRUGS
28.61 Lovastatin
A 1998 study reported that concentrations of Lovastatin, induced apoptosis (cell death) in human malignant mesothelioma cell lines. Mesothelioma cell viability was decreased in a dose-dependent manner by Lovastatin. Rubins (18) The reasons why more research has not been performed on Lovastatin for mesothelioma are unclear and are likely to be more economic than medical. Here, too, the prospect of developing a cure for a rare disease, may not provide sufficient incentive for expensive clinical trials and product development, which may not be successful.
28.62 Need for More Research Funds
Manning’s found a substance called NS 398 inhibited mesothelioma in a laboratory. I would make sense to have the substance developed into a drug and tested in clinical trials. Because of mesothelioma’s relative rarity, pharmaceutical companies have not moved quickly to develop drugs to attack the disease, and more money for research is needed.
Generally, the companies have developed drugs for more prevalent diseases
28.7 SV 40 AND MESOTHELIOMA
28.71. What is SV 40
Simian virus 40 (SV40), is a virus associated with monkeys which has been recently associated with the development of mesothelioma. Some suggest that SV 40 can in contact with humans through contaminated polio vaccines. Polio vaccine was grown on the kidneys of rhesus monkeys. Brierly, (12)
SV 40 has been found in mesothelioma cells, animal studies and human cell biopsies. Foddis found that "SV40, a DNA tumor virus present in approximately 50% of mesothelioma biopsies in the USA." (4). Klein states, "In 1994, PCR and protein studies suggested that SV40 DNA sequences and proteins were present in 29/48 (60%) USA human mesothelioma samples." McLaren found SV 40 in Australian mesothelioma tissue:
"We examined five human mesothelioma cell lines that were established in our laboratories. In addition, we examined several tumour biopsies from seven different patients. SV40 like sequences were present in all the cell lines and in at least one sample from each of the patients examined. CONCLUSIONS: The large T antigen of SV40 or an SV40 like virus is expressed in Australian mesotheliomas and therefore could be aetiologically-associated with tumourigenesis."
Results have not been uniform- "a study in 1996 and a presentation made at the International Mesothelioma Interest Group, IMIG in 1997 failed to detect SV40 in mesotheliomas." Klein (5). This has prompted some discussion of the pathological techniques to ascertain the presence of SV 40.
We studied tissue sections from 18 paraffin embedded mesothelioma specimens diagnosed by the Pathology Department of S. Chiara Hospital of Pisa. Using PCR analysis and Southern blot hybridization we examined the specimens for the DNA regulatory region of the virus. 10/18 (55.5%) of the samples tested contained SV40 DNA regulatory sequences, and of these positive samples, 80% were found to contain Tag sequences by PCR and Southern Blot hybridization. These results confirm that SV40 can be amplified and detected in paraffin embedded mesothelioma samples.
28.72 Relationship to Prognosis
McLaren found that levels of SV 40 were a negative factor in length of survival of mesothelioma patients indicating that the drug played a role in the pathogenesis of the disease.
28.73 SV 40 and Tumor Suppressor Genes
At its simplest level, cancer arises from the triggering of a growth factor and the inactivation of a tumor suppressor gene which would normally act as a brake. P53 is the most well-known tumor suppressor gene with its absence or mutation playing a role in many cancers. P 53 may trigger apoptosis or cell death of genes with abnormalities, and otherwise inhibit stop the abnormal reproduction which is cancer. In this delicate and complex system, SV 40 triggers Tag which in turn may frustrate the normal functioning of tumor suppressor genes.
"The simian virus 40 (SV40) oncoprotein large T antigen (Tag) plays a crucial role in the transformation of human cells and causes cell-cycle derangement of human mesothelial cells (HMC) . The effects of Tag are caused by its ability to bind the tumor suppressor gene products p53 and retinoblastoma family (Rb)proteins." Thus SV 40 is an anti-tumor suppressor gene.
28.74 Significance of P 53 and Rb in Mesothelioma Continues to be Debated
P53 and RB are gene commonly associated with the development of various cancers including non-small cell lung cancer. Boccheta writes, "p53 plays an important role in down-regulating the replication of SV40 genomes in infected HM and in preventing HM lysis." (1). However, some suggest that the significance of P53 and RB are unclear in mesothelioma See Waheed 12 ("These neoplasms are unique in that they rarely if ever exhibit Rb and p53 mutations, which frequently disrupt G1 restriction point control in thoracic malignancies ; these observations suggest that growth constraints mediated by these tumor suppressor genes are circumvented by mechanisms more subtle than those typically observed in solid tumors").
28.741 Animal Studies of SV 40
Bocchetta writes, "SV40 is highly oncogenic in rodents. We found that intracardial injection of SV40 induced MM (malignant mesothelioma) in 60% of hamsters, whereas intrapleural injection caused 100% incidence of MM in 3-7 months." Bocchetta (1). "Rat pleural mesothelioma cells expressing SV40 T exhibit disrupted cell cycle progression, abnormal mitoses, and aneuploidy." Waheed
28.75 SV 40 and Growth Factors
28.751 Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor or VEGF is associated with the spread of lung and other cancers. Recent studies have identified a connection between VEGF and SV 40. "Vascular endothelial growth factor (VEGF), an important angiogenic factor, regulates cell proliferation, differentiation, and apoptosis (programmend cell death) through activation of its tyrosine-kinase receptors, such as Flt-1 and Flk-1/Kdr. Human malignant mesothelioma cells (HMC), which have wild-type p53, express VEGF and exhibit cell growth increased by VEGF. Here, we demonstrate that early transforming proteins of simian virus (SV) 40, large tumor antigen (Tag) and small tumor antigen (tag), which have been associated with mesotheliomas, enhanced HMC proliferation by inducing VEGF expression. SV40-Tag expression potently increased VEGF protein and mRNA levels in several HMC lines." Catalano (2)
28.752 Hepatocyte Growth Factor
While the association between VEGF and cancer
metastasis is well-known and documented, recent research discovered a connection
with a lesser know growth factor.
"Recent studies suggested that simian virus 40 (SV40) may cause malignant
mesothelioma, although the pathogenic mechanism is unclear. We found that in
SV40-positive malignant mesothelioma cells, the hepatocyte growth factor (HGF)
receptor (Met) was activated."
28.76 Teleromerase
Imagine cutting one inch off a 10 inch stick, ultimately the stick would disappear. Each cell has a predetermined number of divisions and a certain size so that divisions must end. Something called teleromerase allows the cells to evade these predetermined restrictions and is associated with cancer. One study found SV-40 "induced telomerase activity in primary human mesothelial cells." Foddis (4)
28.77 Asbestos and SV 40
Asbestos is the chief cause of mesothelioma. What is the connection between asbestos and SV 40. One hypothesis, "Asbestos appears to increase SV40-mediated transformation of human mesothelial cells in vitro, suggesting that asbestos and SV40 may be cocarcinogens." Carbone (3). The cocarcinogen hypothesis is consistent with the long latency of mesothelioma, making it likely that multiple carcinogens are needed for cancer transformation. Since only a portion of those exposed contract lung cancer, it makes sense that a genetic weakness is a contributing factor in the disease. "The role of asbestos in causing MM has been firmly established epidemiologically; however, it has been difficult to reconcile the epidemiological findings with the inability of asbestos to transform mesothelial cells in tissue culture." Bocchetto (1)
Here is a similar theory:
"Mesothelioma, a malignancy associated with asbestos, has been recently linked to simian virus 40 (SV40). We found that infection of human mesothelial cells by SV40 is very different from the semipermissive infection thought to be characteristic of human cells. Mesothelial cells are uniformly infected but not lysed by SV40, a mechanism related to p53, and undergo cell transformation at an extremely high rate. Exposure of mesothelial cells to asbestos complemented SV40 mutants in transformation. Our data provide a mechanistic explanation for the ability of SV40 to transform mesothelial cells preferentially and indicate that asbestos and SV40 may be cocarcinogens." Boccheto (1)
28.78 SV 40 Treatment Options
Determining that a particular gene, enzyme, or growth factor plays a role in the creation or spread of disease is only the first step in crafting a cure or remedy. One must determine if the damage can be corrected, create a delivery system for an anti-virus or other suppressant, and determine that the new drug carries no untoward side effects.
28.781 Vaccine
One possibility is a vaccine:
"The identification of SV40 as a possible cause of human cancer leads to the question of whether the unique properties of the virus can be exploited to treat patients with SV40-positive mesotheliomas, which are otherwise refractory to successful intervention. A modified SV40 T antigen, from which the transforming domains have been removed, has been cloned into a vaccinia virus vector and tested in animal tumor model systems. It has been shown to be effective against both subsequent tumor challenge and pre-existing tumors. Thus, the potential exists for use of such a vaccine in mesothelioma patients."
Another writer reports success in cell studies:
An adenoviral vector expressing an antisense transcript to SV40 early region inhibited T antigen expression and mediated significant growth inhibition and apoptosis in T-antigen-positive mesothelioma cells and SV40-transformed COS-7 cells. Abrogation of T/t antigen expression coincided with enhanced p21/WAF-1 expression, suggesting that restoration of p53-mediated pathways may have contributed to the growth inhibition and apoptosis induced by the antisense construct. These effects were not observed after similar treatment of mesothelioma or lung cancer cells containing no SV40 DNA sequences. Collectively, these data suggest that SV40 oncoproteins contribute to the malignant phenotype of pleural mesotheliomas and indicate that interventions designed to abrogate their expression may be efficacious in the treatment of individuals with these neoplasms."
28.782 Why Isn’t More Money Spent Searching for a Cure for Mesothelioma
The Waheed study was done in 1999; why aren’t we close to a clinical trial of an SV40 anti-virus. While millions, indeed, billions have been spent on litigating asbestos mesothelioma cases, a far lesser amount has been spent on research on this disease. Given the relatively small number of people with mesothelioma, a drug which addressed the disease might not be as profitable as drugs which attacked more prevalent diseases. One hopes that additional public pressure will prompt needed research.
28.783 Assessing SV 40 values and treatment.
Instinctively, one might ask if patients should be tested for SV 40 and those testing positive should receive targeted treatment. Some analogous issues are presented with the drug Iressa, which targets involves the epidermal growth factor, related to the development and spread of lung cancer. While the drug targets the epidermal growth factor receptor, treatments are not discriminating based on levels of that growth factor.
28.784 P16 Tumor Supressor Gene
P16ink4a is a lesser known tumor suppressor gene which seemingly plays a greater role in mesothelioma. "Examination of p16INK4a was suggested by the frequent loss of the chromosome 9p region encoding p16INK4a and p14ARF in primary mesothelioma and in mesothelioma cell lines, as well as the association of p16INK4a loss or methylation with extension of lifespan in culture."
SV 40 Section References
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2. Catalano, Enhanced expression of vascular endothelial growth factor (VEGF) plays a critical role in the tumor progression potential induced by simian virus 40 large T antigen, Oncogene 2002 Apr 25;21(18):2896-900
3. Carbone, The pathogenesis of mesothelioma, Semin Oncol 2002 Feb;29(1):2-17
4. Foddis, SV40 infection induces telomerase activity in human mesothelial cells, Oncogene 2002 Feb 21;21(9):1434-42
5. Klein, Association of SV40 with human tumors, Oncogene 2002 Feb 14;21(8):1141-9
6. Caccioti, SV40 replication in human mesothelial cells induces HGF/Met receptor activation: a model for viral-related carcinogenesis of human malignant mesothelioma, Proc Natl Acad Sci U S A 2001 Oct 9;98
7. McLaren, Simian virus (SV) 40 like sequences in cell lines and tumour biopsies from Australian malignant mesotheliomas, Aust N Z J Med 2000 Aug;30(4):450-6
8. Procopio, Simian virus-40 sequences are a negative prognostic cofactor in patients with malignant pleural mesothelioma, Genes Chromosomes Cancer 2000 Oct;29(2):173-9
9. Stearly, The Forty Year Legacy of Tainted Polio Vaccine, www.ioa.com/~dragonfly/vaccine2.html
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13. Lixin, Asbestos induction of extended lifespan in normal human mesothelial cells: interindividual susceptibility and SV40 T antigen, Carcinogenesis, Vol. 20, No. 5, 773-783, May 1999
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