CHAPTER 28:  IMMUNOTHERAPY AND GENE THERAPY FOR MESOTHELIOMA

 

                                                                                   

 

28.1  IMMUNOTHERAPY tc \l2 "28.1  IMMUNOTHERAPY  

 

     Immunotherapy was studied for a variety of cancers.  It has been a potential treatment for mesothelioma. 

 

The rationale for immunotherapy is the existence of immune abnormalities in patients 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).

 

28.11  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 seen.  In the laboratory, low concentrations of Interferon help boost the power of natural killer T cells and with some tumors, interferons can help inhibit metastasis.  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  Mechanism of Interferon

 

     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.  .... 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.” 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

  

    Significant side effects have been reported with Interferon so defining the maximum tolerable dose is no easy task.  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.  A Turkish study found moderately favorable results, a response rate of 24% combining Interferon with Cisplatin. Metintas (14).  Some cell studies support the hypothesis that Interferon can improve the efficacy of chemotherapy.  One study reported, AA 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  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:

 

a Phase II study was conducted, in which IL-2  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 {suggest} that intrapleural administration of IL-2 is well tolerated and has antitumor activity in patients with MPM.  Astroul (7).

 

28.3  EPIDERMAL GROWTH FACTOR INHIBITORS

        AND MESOTHELIOMA                              

 

28.31  Cell Studies  

 

     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.  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, and shown substantial success upon EGFR positive patients.  (See our chapters on EGFR inhibitors and non-smoker’s cancer).  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 Zymed^TM 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.@  (13 (egfrinfo.com).

 

      A recent presentation found that asbestos prompted production of the

epidermal growth factor and this could be duplicated in the laboratory: 

 

ADVANCE  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. 

 

“Malignant pleural mesothelioma (MPM) expresses high levels of epidermal growth factor receptor (EGFR), and preclinical studies have identified antitumor activity of EGFR tyrosine kinase inhibitors (TKIs) in MPM.”  Garland (20).

 

                28.32.  Human Studies

 

     Investigation is continuing.  Initial studies have been disappointing and Garland’s study with Tarceva found little impact.  Strangely, the study did not appear to test the patients to determine who was EGFR positive.  With lung cancer, Tarceva has shown response rates exceeding 50% for EGFR positive patients but only 10% for those who were not.  One study examined overexpression finding that many tumors express EGFR, but found little correlation between that expression and response.  Govindan (21).

     Right now despite the cell studies showing some promise, the human studies have been disappointing.   

 

28.4  COX-2 INHIBITORS AND MESOTHELIOMA

                28.41 Overview

 

Cox-2 is produced in response to inflammatory process.  As our section on cox-2 inhibitors discusses (16.4) Cox-2 is associated with various carcinogenic processes.  "Cyclooxygenase-2 (COX-2) plays an important role in solid tumor growth, invasiveness, and angiogenesis."  Edwards (17).  Cox-2 inhibitors like Celebrex present the possibility of inhibiting some cancer processes.

                28.42 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 demonstrates 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."

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).    Celebrex and other Cox-2 inhibitors should be tested on mesothelioma, probably in conjunction with other established therapies.

   

28.5  OTHER DRUGS

 

28.51  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. 

 

28.52  Need for More Research Funds

 

     Manning=s found a substance called NS 398 inhibited mesothelioma in a laboratory.  It 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

 

28.6  SV 40 AND MESOTHELIOMA  

 

28.61  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 come into 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 ASV40, a DNA tumor virus was present in approximately 50% of mesothelioma biopsies in the USA.@  (4).  Klein states, AIn 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-  Aa 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 SV40.   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.

 

28.62  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. 

 

28.63  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.  P53 may trigger apoptosis or cell death of genes with abnormalities, and otherwise inhibit or 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.

 

     However, some suggest that the significance of P53 and RB are unclear in mesothelioma.  See Waheed 12. (AThese 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.@)        

 

       28.64  Animal Studies of SV 40 

 

     Bocchetta writes, ASV40 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).  ARat pleural mesothelioma cells expressing SV40 T exhibit disrupted cell cycle progression, abnormal mitoses, and aneuploidy.@  Waheed.

 

28.65  SV 40 and Growth Factors

 

28.651  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).

 

28.652  Hepatocyte Growth Factor

 

     While the association between VEGF and cancer metastasis is well-known and documented, recent research discovered a connection with a lesser known 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.@

 

28.67  Asbestos and SV 40

 

    Asbestos is the chief cause of mesothelioma.  What is the connection between asbestos and SV 40?  One hypothesis, AAsbestos 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.  AThe 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).  e 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).        

 

28.68  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. 

 

28.681  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.@

 

28.682  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.

 

28.683  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 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. 

 

28.684  P16 Tumor Supressor Gene

 

     P16ink4a is a lesser known tumor suppressor gene which seemingly plays a greater role in mesothelioma.  AExamination of p16^INK4a was suggested by the frequent loss of the chromosome 9p region encoding p16^INK4a and p14^ARF in primary mesothelioma and in mesothelioma cell lines, as well as the association of p16^INK4a loss or methylation with extension of lifespan in culture.@

 

SV 40 SECTION REFERENCES

 

1.       Bocchetta, Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity, Proc Natl Acad Sci U S A 2000 Aug 29;97(18):10214-9.

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.

10.     Cristaudo, SV40 can be reproducibly detected in paraffin-embedded mesothelioma samples, Anticancer Res 2000 Mar-Apr;20(2A):895-8.

11.     Imperiale, Prospects for an SV40 vaccine, Semin Cancer Biol 2001 Feb;11(1):81-5.

12.     Waheed, Antisense to SV40 early gene region induces growth arrest and apoptosis in T-antigen-positive human pleural mesothelioma cells, Cancer Res 1999 Dec 15;59(24):6068-73.

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.

14.     Cristaudo, SV40 Enhances the Risk of Malignant Mesothelioma among People  Exposed to Asbestos: A Molecular Epidemiologic Case-Control Study, Cancer Res. 2005 Apr 15;65(8):3049-52

 

OTHER REFERENCES

 

1.       Monnert, Intrapleural Infusion of Activated Macrophages and -Interferon in Malignant Pleural Mesothelioma,  Chest. 2002;121:1921-1927.

2.       Goey, Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I-II study, Br J Cancer 1995 Nov;72(5):1283-8.

3.       Hand, Interferon (IFN)-alpha and IFN-gamma in combination with methotrexate: in vitro sensitivity studies in four human mesothelioma cell lines, Anticancer Drugs 1995 Feb;6(1):77-82

4.       Boutin, Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma.Cancer 1994 Nov 1;74(9):2460-7.

6.       OReilly, A phase II trial of Interferon Alpha-2a and Carboplatin in patients with Advanced Malignant Mesothelioma. Cancer Invest, 1999, 17:3, 195-200.

7.       Astoul, Intrapleural administration of interleukin-2 for the treatment of patients with malignant pleural mesothelioma: a Phase II study, Cancer 1098 Nov, 83:10, 2099-104.        

8.       Amodio, Gemcitabine in peritoneal mesothelioma: a case report]   Clin Ter, 1998 Nov, 149:6, 447-51.

9.       Nakano, Cisplatin in combination with irinotecan in the treatment of patients with malignant pleural mesothelioma: a pilot phase II clinical trial and pharmacokinetic profile.  Cancer, 1999, Jun, 85:11, 2375-84.

10.     Porohit, Weekly systemic Combination of Cisplatin and Interferon Alpha 2a in Diffuse Malignant Pleural Mesothelioma, Lung Cancer, 1998, Nov. 22.:2, 119-25. 

11.     Ryan & Vogelzang, A Review of  Chemotherapy trials for Malignant Mesothelioma, Chest, 1998, Jan. 113:1, Supp. 66s-73s.@   

12.     Ardizzoni, Systemic Drug Therapy of Malignant Pleural Mesothelioma, Monaldi Arch Chest Dis, 1998 Apr, 53:2, 236-40.

13.     Astra-Zeneca publishers of Signal, a medical journal devoted to epidermal growth factor research. 

14.     Metitinas, , Cisplatin, Mitomycin, and Interferon-alpha2a combination chemoimmunotherapy in the treatment of diffuse malignant pleural mesothelioma. Chest, 19922.66.