Plevitrexed

To provide therapeutic alternatives to intravenous colon chemotherapy major recent research is focusing on the development of oral chemotherapeutic agents with the intention to improve the quality of life of patients. Initially 5-fluorouracil was most commonly used for the treatment of colorectal cancer but currently oxaliplatin and irinotecan are also available. The majority of these new drugs are pyrimidines and their analogs. The rationale for using oral anticancer agents is discussed and new drugs, such as farnesyl protein transferase inhibitor S-1, rubitecan, ZD9331, MMI-166, eflornithine, sulindac, and oral camptothecin analogs, among others, are presented with the results of their preclinical and clinical developments. This article focuses on the advancement of clinical development and also discusses the relative merits and demerits of these agents. The accelerated approval of these agents by regulatory authorities is supported by survival benefit, response rate and time to progression.

The goal of this report is to review the activity of promising antifolate and folate receptor agents being developed for ovarian cancer including thymidylate synthase inhibitors, antifolate receptor antibodies, and folate-chemotherapy conjugates.

A literature search was performed over the last 5 years using the terms "folate receptor" and "ovarian cancer" and those that specifically addressed the MOA were included. Abstracts presented within the last 3 years were also searched and included in this review where appropriate.

Thymidylate synthase inhibitors are a promising avenue for ovarian cancer treatment. Phase II trials have shown pemetrexed to have activity in patients with platinum resistant ovarian cancer. Several other thymidylate synthase inhibitors are in the early phase of development including BGC 945 and ZD-9331. Monoclonal antibodies that target the folate receptor have also shown potential in the development of ovarian cancer therapies. Farletuzumab is one of these antibodies. A recent phase III trial found that farletuzumab in combination with carboplatin and taxane did not meet the study's primary endpoint of progression-free survival (PFS). The post hoc exploratory analysis showed, however, a trend toward improved PFS in some patient subsets and further analysis is ongoing. The folate receptor is also utilized through folate conjugates. Vintafolide is one such agent which is currently in phase III development. Encouraging data from phase II trials showed an improvement in PFS from 2.7 months to 5 months. Folate can also be conjugated to radioisotopes for both therapeutic and imaging purposes, and early studies have shown correlation with amount of disease to therapy response.

Folate targeted agents continue to show promising antitumor activity in ovarian malignancy and initial clinical experience has demonstrated favorable toxicity profiles. Further development and resources targeted toward these therapies appear to be warranted.