Pocket Drug Guide

Overview

Apoptosis, or programmed cell death, represents a universal and efficient cellular suicide pathway. As an understanding of apoptosis’s vital role in normal cellular development has deepened, numerous genes that encode apoptotic regulators — some of which represent familiar oncogenes or tumor suppressor genes — have been identified.

Targeting apoptosis succeeds only if the therapeutic index is good enough to selectively destroy cancer cells rather than normal cells. In drug-curable malignancies, such as common pediatric leukemias and certain solid tumors, apoptosis is a prominent mechanism associated with the induction of tumor remission. Many cytotoxic agents’ ultimate mechanism of action takes place via the general apoptotic pathway.

Mechanism Of Action

Apoptosis is an evolutionarily conserved cell-death pathway that occurs in a variety of physiological situations. An apoptotic stimulus induces an initiation and commitment phase, followed by a degradation phase. This last stage is regulated by cysteine proteases (caspases 1-14) and follows a characteristic pattern of the following morphological changes: membrane ruffling; mitochondrial dysfunction; cytoplasmic and organelle shrinkage; nuclear contraction; and endonuclease activation, resulting in DNA fragmentation. Two central pathways mediate apoptosis: the type I extrinsic or death receptor pathway, which generates an apoptotic signal following the aggregation of death ligands; and the type II or intrinsic pathway, which signals through mitochondria. In some cases, type I activation may also proceed down the mitochondrial pathway.

A drug that activates apoptosis might achieve a suitable therapeutic index in several ways. First, it might activate a death cascade via a drug target that is uniquely expressed in a cancer cell. Alternatively, it might be delivered to the target tissue in a manner that is selective for the cancer cell. A third possibility — and perhaps the most promising one — is that such a drug could exploit a pathway activated by oncogenes to provoke apoptosis selectively in cancer cells. It is now clear that oncoproteins can interact with apoptotic regulatory pathways. Thus, overexpression of Myc sensitizes cells to a wide assortment of apoptotic triggers, probably reflecting the role of apoptosis in the intracellular immunity that prevents normal cells from persisting in the body once they acquire cancer-causing genetic defects. However, many human tumors that overexpress Myc are highly resistant to apoptotic triggers, probably owing to a variety of downstream lesions that blunt the death pathway. Still, the recognition that oncogenes can sensitize cells to proapoptotic treatments suggests that if such lesions can be circumvented, drugs that induce cell death could prove highly selective for cancer cells.

Arsenic Trioxide

Arsenic trioxide (Cell Therapeutics’ Trisenox) was commonly used in the treatment of leukemia during the first half of the 20th century, prior to the advent of busulfan.

Arsenic trioxide has been marketed for the treatment of acute promyelocytic leukemia (APL) in the United States since 2000 and in Europe since 2002. In the late 1990s, several trials investigated the potential of arsenic to treat chronic-phase chronic myelogenous leukemia in patients who have failed interferon-a. However, the launch of imatinib in 2001 rendered these data irrelevant almost before they were published. Phase II and initial Phase III data from these trials found that arsenic achieves a major cytoge-netic response in 60% of interferon-a intolerant/resistant patients and in 80% of newly diagnosed patients (Tallman M, 2000). More recently, preclinical and clinical investigators have pursued a more clinically relevant role for arsenic trioxide by testing the agent in blastic-phase disease, in imatinib-resistant cells/patients, and in combination with imatinib.

In a small Phase I/II study, six patients with chronic-phase imatinib-resistant or relapsed chronic myelogenous leukemia received arsenic trioxide and imatinib in an attempt to restore hematologic response and/or induce major cytogenetic response. Resistant/relapsed disease was defined as either “lack of major cytogenetic response after six months of therapy” or “loss of previous response, with or without hematologic response.” Imatinib was administered at 400 mg per day, with arsenic trioxide given as a loading dose (0.25 mg/kg/day for five days) followed by maintenance therapy (0.25 mg/kg/day two days/week). According to investigators, treatment was well tolerated with predictable and manageable side effects. Significant toxicities included grade 3 shortness of breath, grade 2 elevations of aspartate amino transferase (AST) and/or amino alanine transferase (ALT), hyperglycemia, lower extremity edema, fatigue, and dyspepsia, each in three or fewer patients. No dose-limiting toxicities were encountered.

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