Anti-cancer drugs
-
Ecteinascidin-743 (ET-743) has shown promise as a new and effective treatment for soft-tissue sarcomas. Two independent, multicenter, Phase II studies have been performed in the USA for patients with unresectable soft-tissue sarcomas (either chemotherapy-naïve or pretreated patients). The patients received ET-743 at a dose of 1500 micrograms/m2 as a 24 h continuous intravenous infusion every 3 weeks on an outpatient basis. ⋯ The side effects were reversible, non-cumulative and manageable. There were no treatment-associated deaths. In conclusion, ET-743 is an active chemotherapeutic agent that can induce objective responses and clinical benefit in a subset of patients with metastatic or advanced soft-tissue sarcoma.
-
Initial evidence of clinical benefit with ecteinascidin-743 (ET-743) in patients with sarcoma was provided during a Phase I pharmacokinetic study in which 52 patients received ET-743 at doses of 50-1800 micrograms/m2 as a 24 h continuous infusion every 3 weeks. Neutropenia and thrombocytopenia were the dose-limiting toxicities; liver toxicity (a severe but transient and reversible increase in transaminase concentrations) was not treatment limiting. In conjunction with results obtained with ET-743 in a compassionate-use program, these indications of activity in heavily pretreated patients with sarcoma prompted initiation of a French multicenter Phase II study of ET-743 in this population. ⋯ Progression-free survival at 6 months was 26.5% and the overall survival rate at 12 months was almost 50%. The response rate was uninfluenced by tumor metastatic site, size or anthracycline sensitivity status. These results, combined with the lack of cumulative toxicity, confirm the role of ET-743 in the treatment of advanced STS.
-
STI571 (imatinib mesylate) is an example of the successful development of a targeted agent. Its target is the constitutively active tyrosine kinase (p210bcr-abl) in a hematologic neoplasm, chronic myelogenous leukemia (CML). ⋯ This article reviews the pre-clinical and clinical development of this agent and also discusses some of the prevailing theories to explain the emerging problem of resistance. Future directions for this drug, possibly directed at other targets, are also discussed.
-
Recombinant rIL-2 was reported to be able to decrease P-glycoprotein (P-gp) expression in cultured cells from human colon carcinoma. P-gp is considered an important factor in the control of Taxol efflux from tumor cells. Based on the premise that Taxol pharmacokinetic parameters could be modified as a result of diminished P-gp expression induced by recombinant interleukin (rIL)-2 and that this might elicit an interaction between the two drugs, we evaluated the pharmacokinetics of a novel strategy combining i.p. immunotherapy with rIL-2 and a cytotoxic agent, Taxol. ⋯ We conclude that rIL-2 pretreatment is able to decrease P-gp activity and paclitaxel metabolism in vivo. This is the first study to demonstrate a decrease in P-gp activity and expression in organs such as the brain in vivo. A novel strategy combining immunotherapy with rIL-2 and a cytotoxic agent could potentially improve clinical results, particularly in brain cancer.
-
Amplification of the human epidermal growth factor receptor-2 (HER2) gene and overexpression of the encoded protein are seen in 20-30% of breast cancers, and are associated with aggressive disease and relatively poor prognosis. Thus, HER2 represents an appropriate target for anticancer treatment and the humanized anti-HER2 monoclonal antibody Herceptin has been developed for this purpose. The efficacy of Herceptin has been confirmed in two pivotal trials-a monotherapy study in 222 women with HER2-positive metastatic breast cancer who had already received one or two chemotherapy regimens for metastatic disease and a study comparing Herceptin plus chemotherapy with chemotherapy alone in 469 patients previously untreated for metastatic disease. ⋯ Most patients respond to conventional supportive treatment. Cardiotoxicity, the most serious adverse event observed, occurred mainly in patients exposed to anthracyclines and was generally manageable. Thus, Herceptin represents a significant development in the management of HER2-positive breast cancer.