Ovarian cancer is a leading cause of morbidity in the female population. Several malignancies arise from the ovary. Epithelial carcinoma of the ovary is one of the most common gynaecologic malignancies and the fifth most frequent cause of cancer death in women, with half of all cases occurring in women over age 65.
Approximately 5% to 10% of ovarian cancers are familial and 3 distinct hereditary patterns have been identified: ovarian cancer alone, ovarian and breast cancers, or ovarian and colon cancers. The most important risk factor for ovarian cancer is a family history of a first-degree relative (mother, daughter, or sister) with the disease. The highest risk appears in women with 2 or more first-degree relatives with ovarian cancer. The risk is somewhat less for women with one first-degree and one second-degree (grandmother, aunt) relative with ovarian cancer. In most families affected with breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage has been found to the BRCA1 locus on chromosome 17q21. BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12.
The lifetime risk for developing ovarian cancer in patients harbouring germ-line mutations in BRCA1 is substantially increased over the general population. Two retrospective studies of patients with germ-line mutations in BRCA1 suggest that these women have improved survival compared to BRCA1 negative women. When interpreting this data, it must be considered that the majority of women with a BRCA1 mutation probably have family members with a history of ovarian and/or breast cancer. Therefore, these women may have been more vigilant and inclined to participate in cancer screening programs that may have led to earlier detection. For patients at increased risk, prophylactic oophorectomy may be considered after the age of 35 if childbearing is complete. However, the benefit of prophylactic oophorectomy has not yet been established. A small percentage of women may develop a primary peritoneal carcinoma, similar in appearance to ovarian cancer, after prophylactic oophorectomy (Xiao, C. et al., 2001). Epithelial carcinomas are the most common types of ovarian cancer. Stromal and germ cell tumors are relatively uncommon and comprise less than 10% of cases.
Ovarian cancer usually spreads via local shedding into the peritoneal cavity followed by implantation on the peritoneum, and via local invasion of the bowel and the bladder. The highly lethal nature of this tumor is due to the absence of symptoms in women with early stages of this disease. The incidence of positive nodes at primary surgery has been reported as high as 24% in patients with stage I disease, 50% in patient with stage II disease, 74% in patients with stage III disease, and 73% in patients with stage IV disease. Tumor cells may also block diaphragmatic lymphatics. The resulting impairment of lymphatic drainage of the peritoneum is thought to play a role in development of ascites in ovarian cancer. Also, transdiaphragmatic spread to the pleura is common.
Prognosis in ovarian cancer is influenced by several factors, but multivariate analyses suggest that the most important favorable factors include younger age, good performance status, cell type other than mucinous and clear cell, lower stage, well differentiated tumor, smaller disease volume prior to any surgical debulking, absence of ascites, and smaller residual tumor following primary cytoreductive surgery. For patients with stage I disease, the most important prognostic factor is grade, followed by dense adherence and large-volume ascites. DNA flow cytometric analysis of stage I and stage IIA patents may identify a group of high-risk patients. Patients with clear cell histology appear to have a worse prognosis. Patients with a significant component of transitional cell carcinoma appear to have a better prognosis.
Although the ovarian cancer-associated antigen, CA 125, has no prognostic significance when measured at the time of diagnosis, it has a high correlation with survival when measured one month after the third course of chemotherapy for patients with stage III or stage IV disease (Rossmann, M. G. et al., 2000). For patients whose elevated CA 125 normalizes with chemotherapy, more than one subsequent elevated CA 125 is highly predictive of active disease, but this does not mandate immediate therapy.
Most patients have widespread disease at the time of diagnosis because ovarian cancer is often asymptomatic in its early stages. Partly as a result of this, yearly mortality in ovarian cancer is approximately 65% of the incidence rate. Long-term follow-up of suboptimally debulked stage III and stage IV patients reveals a 5-year survival rate of less than 10% even with platinum-based combination therapy. Nevertheless, early stages of the disease are curable in a high percentage of patients.
At present the treatment for late stage ovarian cancers involves a total abdominal hysterectomy, careful examination of serosal surfaces, and attempts to debulk all gross disease usually followed by combination chemotherapy that includes a platinum analogue. The survival rate is then between six to forty month, long term survival being less than ten percent.
There has been ongoing research with the aim of identifying molecules that are differentially expressed in benign and malignant ovarian tumors.
Ovarian carcinomas have been found to express the integrin α2β1 (Moser, T. L. et al., 1996; Cannistra, S. A. et al., 1995; Bartolazzi, A. et al., 1993). α2β1 promotes metastatic dissemination of human ovarian epithelial carcinoma via specific binding interactions with type 1 collagen (Schiro, J. A. et al., 1991; Cardarelli, P. M. et al., 1992). Up-regulated surface-expression of integrin α2β1 has also previously been observed on human gastric carcinoma.
The interaction of α2β1 with type 1 collagen likely plays a critical role in peritoneal seeding as well as in metastasis, and over expression of α2β1 has been shown to induce metastatic properties in non-metastatic cells (Chan, B. M. et al., 1991). Blocking of α2β1 has been shown to largely inhibit adhesion of ovarian carcinomas by type 1 collagen.
Viruses capable of inducing lysis of malignant cells through their replication process are known as oncolytic viruses. Most oncolytic viruses require proliferation in the same species or cell lineage. Infection of a cell by a virus involves attachment and uptake into the cell which leads to or is coincidental with uncoating of the viral capsid, and subsequently replication within the cell.
Oncolytic viruses assessed for capacity to kill cancer cells have included the adenovirus subtype Egypt 101 virus which showed oncolytic activity in the HeLa uterine/cervix cancer cell line, mumps virus for treatment of gastric carcinoma, uterine carcinoma and cutaneous carcinoma, Newcastle Disease Virus (NDV), influenza virus for treatment of ovarian cancer, and adenovirus for treatment of cervical carcinoma (Nemunaitis J; 1999).
Other reports have indicated that adenoviruses and attenuated poliovirus recombinants may have use in the treatment of malignant glioma cells (e.g. Andreansky S. S., 1996), and that reovirus shows lytic capability in human U87 glioblastoma cells and NIH-3T3 cells with an activated Ras signalling pathway (e.g. Strong J. E. et al, 1998).
A vaccinia oncolysate has also been used in clinical trials to treat melanoma (Stage II) patients (Nemunaitis J., 1999). Modified, non-neurovirulent Herpes simplex viruses (HSV) have been reported as showing promise for the treatment of brain tumors including intracranial melanoma, and subcutaneous human melanoma (Randazzo B. R., 1997), while adenovirus infection has been reported to enhance killing of melanoma cells by the plant mitotoxin, saporin (Satyamoorthy K., 1997).
The receptor on target cells recognised by adenovirus differs for different adenovirus types. That is, adenovirus subgroups A, C, D, E and F for instance recognise the CAR receptor while Adenovirus type 5 (subgroup C), Adenovirus type 2 (subgroup C) and Adenovirus type 9 (subgroup D) recognise major histocompatibility class II molecule, αmβ2 and αv integrins, respectively. The CAR receptor is known to be expressed on melanoma cell lines.
Heparan sulfate is recognised by Herpes simplex types 1 and 2 and human herpes virus 7, Adeno-associated virus type 2. The receptor for human Herpesvirus 7 is CD4 while Epstein-Barr virus recognises complement receptor Cr2 (CD21). Poliovirus type 1 and 2 recognise poliovirus receptor (Pvr) for cell adhesion while reovirus recognises sialic acid. Influenza A and B virus recognise the sialic acid N-acetyl neuraminic acid for cell adhesion In contrast, influenza type C virus recognises the sialic acid 9-O-acetyl neuraminic acid. Vaccina virus recognises both epidermal growth factor receptor and heparan sulfate. Coxsackievirus A13, A15, A18 and A21 recognise ICAM-1 and the complement regulatory protein DAF (CD55) (see eg. Shafren D. R., et al 1997). International Patent Application No. PCT/AU00/01461 describes the administration of Coxsackievirus which recognises ICAM-1 for cell infectivity to a subject for lysis of melanoma cells express ICAM-1. DAF is also recognised by Enterovirus 70 (see eg. Flint S J, et al (2000) Principles of Virology: molecular biology, pathogenesis and control, ASM Press, Washington).
A study evaluating the adaptability of ovarian cells to subculture and their potential use for the detection of viruses has been reported (Harris, R E and Pindak, F F, 1975). In the study, normal ovarian cell cultures were challenged with a broad range of viruses including Picornavirus such as Coxsackievirus A, Coxsackievirus B, Poliovirus, Echovirus and Cardiovirus and serotypes thereof,; Paramyxovirus such as Newcastle disease virus, Measles virus, distemper virus; Adenovirus human subgroup serotypes 3, 4, 7 and 21; Herpes simplex virus, Type 1; Togavirus such as Sindbis and Mararo; Reovirus serotypes 1 to 3; and Vaccinia virus. The study demonstrated that cells from human ovaries can be grown long-term in cell culture and may be passaged an undetermined number of times for the propagation of various vises in vitro and proposed that such cultures may be useful for the purpose of studying viral pathogenisis and pathology of viral infection. The report further suggested that as some viruses such as poliovirus and vaccinia have been shown to cross the human placenta and infect the fetus, the study of viral interactions with normal ovarian cells in culture may be a means of furthering teratogenic investigations.
Metastatic tumor spread is a pathological process associated with a series of adhesion/de-adhesion events coupled with regulated tissue degradation. Adhesion to and migration through the extracellular matrix is essential for tumor invasion. Despite progress being made in the treatment of malignancies, the treatment of cancer including ovarian malignancies presents a major challenge for research and there remains a need for alternatives to existing therapy approaches.