Patterns of cell death have been divided into apoptosis, which is actively executed by specific proteases, the caspases, and accidental necrosis. However, there is now accumulating evidence indicating that cell death can occur in a programmed fashion but in complete absence and independent of caspase activation. Alternative models of programmed cell death (PCD) have therefore been proposed, including autophagy, paraptosis, mitotic catastrophe, and the descriptive model of apoptosis-like and necrosis-like PCD. Caspase-independent cell death pathways are important safeguard mechanisms to protect the organism against unwanted and potential harmful cells when caspase-mediated routes fail but can also be triggered in response to cytotoxic agents or other death stimuli. As in apoptosis, the mitochondrion can play a key role but also other organelles such as lysosomes and the endoplasmic reticulum have an important function in the release and activation of death factors such as cathepsins, calpains, and other proteases. Here we review the various models of PCD and their death pathways at molecular and organelle level and discuss the relevance of the growing knowledge of caspase-independent cell death pathways for cancer.

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Purpose: BMS-275183, an orally administered C-4 methyl carbonate paclitaxel analogue, showed promising activity in a phase I trial investigating a weekly treatment regimen, but was associated with a relatively high incidence of neuropathic side effects.The current dose escalation phase I trial was initiated to investigate whether twice weekly administration of BMS-275183 would improve its safety and tolerability. Additionally, the pharmacokinetics and possible antitumor activity were studied. Experimental Design: A cycle consisted of 4 weeks (i.e., eight twice weekly oral doses). The starting dose was 60 mg/m 2 and the dose was increased by 20 mg/m 2 increments. Cohorts consisted of three patients and were expanded to at least six patients when toxicity was encountered. Plasma pharmacokinetics were done on days 1and 15. Results: A total of 38 patients were enrolled. The maximum tolerated dose was 100 mg/m 2 twice weekly. Seventeen patients were treated at the maximum tolerated dose; 3 of 17 patients experienced a dose-limiting toxicity, consisting of a combination of neutropenia, neuropathy, and diarrhea. BMS-275183 seemed to have a considerably lower incidence of neuropathic side effects compared with the weekly treatment regimen. Confirmed partial responses were observed in two patients with non^small cell lung cancer, one patient with prostate cancer, and one patient with melanoma. In addition, a long-lasting prostate-specific antigen response was observed in a patient with prostate carcinoma with nonmeasurable disease. Conclusions: BMS-275183 is preferably given in a twice weekly regimen and has considerable antitumor activity. A phase II trial in non^small cell lung cancer using the twice weekly schedule has been initiated.

Purpose: BMS-275183 is an orally administered C-4 methyl carbonate analogue of paclitaxel.We did a dose-escalating phase I study to investigate its safety, tolerability, pharmacokinetics, and possible antitumor activity. Experimental Design: A cycle consisted of four weekly doses of BMS-275183. The starting dose was 5 mg, which was increased by 100% increments (i.e., 5, 10, 20 mg/m 2 , etc.) in each new cohort consisting of one patient. Cohorts were expanded when toxicity was encountered, and 20 patients were treated at the maximum tolerated dose (MTD). Plasma pharmacokinetics were done on days 1and 15. Results: A total of 48 patients were enrolled in this trial. Dose-limiting toxicities consisted of neuropathy, fatigue, diarrhea, and neutropenia. First cycle severe neuropathy was reported in four patients treated at 320 (n = 1), 240 (n = 2), and160 mg/m 2 (n = 1), whereas eight patients treated at dose levels ranging from 160 to 320 mg/m 2 experienced grade 2 neuropathy in cycle one. The MTD was 200 mg/m 2 , as 3 of 20 patients experienced grade 3 or 4 toxicity in cycle one [fatigue (n = 2), and neutropenia/diarrhea (n = 1)]. BMS-275183 was rapidly absorbed with a mean plasma half-life of 22 hours. We observed a significant correlation between drug-exposure and toxicity. Tumor responses were observed in 9 of 38 evaluable patients with non^small cell lung cancer, prostate carcinoma, and other tumor types. Conclusions: BMS-275183 is generally well tolerated on a weekly schedule. The main toxicity is peripheral neuropathy, and the MTD is 200 mg/m 2 . Promising activity was observed in several tumor types, and a phase II trial in non^small cell lung cancer has been initiated.