Protein members of the apoptotic pathway are found to be dysregulated in many cancers. Chronic lymphocytic leukemia cells, in particular, overexpress antiapoptotic proteins, thus avoiding susceptibility to cell death chronic lymphocytic leukemia’s biology, therefore, makes it an attractive target for apoptosis-inducing agents.
Mechanism Of Action
Apoptosis is the mechanism by which cells undergo programmed cell death. It is a highly ordered and complex cascade with many regulatory checkpoints. Characteristic features include DNA condensation and membrane blebbing.
Salmedix’s SDX-101 is a small-molecule, orally administered, pro-apoptotic agent that is the R-isomer of etodolac, a marketed anti-inflammatory drug. The marketed drug is a mixture of SDX-101 and its isomer. Salmedix has completed a Phase Ib/IIa nonrandomized, multicenter, dose-escalation trial of SDX-101 in chronic lymphocytic leukemia in the United States.
Researchers presented data on 40 patients split into cohorts of 6-8, treated with doses of 600, 800 ,Italy, 000 ,Italy, 200 ,Italy, 800, or 2,400 mg twice daily for eight weeks, with a four-week post-treatment follow-up. The median age was 62.9, and 25% were Binet stage A-progressive, 63.5% Binet B, and 12.5% Binet C. Both untreated (55%) and previously treated (32% one prior therapy, 10% two, and 3% three) patients were enrolled, and the majority (82.5%) had a good performance status. Clinically relevant reductions (defined as >25%) in absolute lymphocyte count (ALC) were observed in 50%, 86%, 88%, and 63% of patients receiving 1,000 , 1,200 , 1,800, or 2,400 mg SDX-101, respectively. Reductions of 42-53% in ALC were achieved within four weeks. No consistent changes in lymphadenopathy or organomegaly were observed, so, based on the NCI’s Working Group criteria, no responses were noted. In addition, no clinically relevant changes in hemoglobin or platelet levels were observed. Adverse events included mild to moderate gastrointestinal toxicity (worse at doses of 1,800 and 2,400 mg), skin rash, and elevated liver enzymes (no dose relationship). Dose-limiting toxicities included deep vein thrombosis in 1 patient at 600 mg and elevated liver enzymes and painful adenopathy in 1 patient at 1,200 mg, all of which resolved upon withdrawal of the drug. Other dose-limiting toxicities included skin rash at 1,800 mg (requiring treatment with antihistamines) and diarrhea at 2,400 mg. No clinically significant myelosuppression, anemia, thrombocytopenia, or gastrointestinal bleeding occurred.
Preclinical data presented at the American Association for Cancer Research (AACR) conference in July 2003 demonstrated that SDX-101 can induce apoptosis in primary chronic lymphocytic leukemia and multiple myeloma cells as well as in various lymphoma cell lines. SDX-101 displayed an additive activity when combined with fludarabine, chlorambucil, or rituximab. In chronic lymphocytic leukemia cells, SDX-101 altered several proteins, including downregulation of the antiapoptosis protein Mcl-1. In addition, the concentration of SDX-101 required to kill cancer cells did not affect normal blood or bone marrow mononuclear cells.
Motexafin gadolinium (Pharmacyclics’ Xcytrin) is the first in a class of investigational drugs known as texaphyrins. The compound is under investigation for several cancers, including chronic lymphocytic leukemia, NHL, pancreatic cancer, non-small-cell lung cancer, and brain metastases. A Phase II clinical trial involving patients with refractory or relapsed chronic lymphocytic leukemia began in the United States in December 2003.
Texaphyrins’ mechanism of action is still under investigation, but motexafin gadolinium is known to target cells that have increased rates of metabolism, such as cancer cells. Once inside the cell, motexafin gadolinium promotes oxidative stress by generating reactive oxygen species; tumor cells treated with this agent undergo apoptosis through the mitochondrial-mediated intrinsic pathway. Motexafin gadolinium is also a radio- and chemosensitizing agent.
Eleven chronic lymphocytic leukemia patients who had failed multiple prior treatment regimens received motexafin gadolinium daily for five days, every three weeks, for two cycles or until disease progression. Pharmacyclics presented preliminary data at the International Congress of Hematologic Malignancies in Canada in March 2004. Researchers observed regression of involved lymph nodes and spleen and a decline in circulating tumor cells in several patients. Motexafin gadolinium was well tolerated. Based on these results, Pharmacyclics plans to expand its trials in chronic lymphocytic leukemia and other non-Hodgkin’s lymphomas to additional centers.
Preclinical data presented at ASH 2003 demonstrated that treatment of lymphoma and myeloma cell lines with motexafin gadolinium resulted in growth inhibition, with a concomitant increase in apoptosis. Lymphoma cell lines were also treated with motexafin gadolinium in combination with other therapeutic agents, including rituximab. Results showed at least additive cytotoxicity, indicating that motexafin gadolinium has the potential to be used as a single agent or in combination.