INTRODUCTION

Cell death contributes to the pathogenesis of a wide variety of diseases. Three distinct forms of cell death are recognized to occur in mammalian cells. Necrosis was traditionally considered an unregulated, rapidly induced form of pathological cell death.

Often resulting from bioenergetic failure of the cell, necrosis is manifested by cell swelling, rupture of the plasma membrane, and disintegration and release of cellular contents, leading to a marked inflammatory response. In contrast, the genetically programmed apoptotic form of cell death requires maintenance of adenosine triphosphate (ATP) levels for execution and is characterized by cell shrinkage, chromatin condensation and internucleosomal DNA fragmentation, and lack of inflammation. Autophagy is another form of cell death that is increasingly recognized as having an important role during development and tumor suppression.

Most, if not all, cancer cells contain aberrations in the genetic pathway of programmed cell death in order to enable deregulated survival. An altered ratio of antiapoptotic to proapoptotic factors can occur due to overexpression of antiapoptotic proteins (via chromosomal translocations or amplifications), loss of proapoptotic proteins (via deletions or loss of function point mutations), or excessive survival signaling (via activating mutations that render survival kinases constitutively active).

This chapter will highlight a few important examples of these aberrations and discuss current therapeutic strategies targeted at modulating cell death summarized in Tables 27.1 and 27.2. Our intent is to provide a broad overview of the approaches being taken to therapeutically regulate cell survival. For a more detailed discussion, readers are referred to specific review articles as indicated.

TABLE 27.1

Strategies to Induce Cell Death

Examples of

Category	Target/Strategy	^Drug	Relevant Diseases	Trial Status	Ref.
Death receptors	TRAIL receptor	TRAIL	Multiple malignancies	Preclinical	11-17
				(in vivo)
IAPs	XIAP antisense		Ovarian cancer, lung	Preclinical	23-25
			cancer	(in vivo)
	Survivin	ISIS 23722	Colon, brain, lung, and	Phase I	26
	antisense		skin cancers
	Small molecule		Multiple malignancies	Preclinical	27-28
	inhibitors of			(in vivo)
	XIAP
	Smac peptides		Glioblastoma, non-	Preclinical	29, 30
			small cell lung cancer	(in vivo)

TABLE 27.1

Strategies to Induce Cell Death

Examples of

Category	Target/Strategy	^Drug	Relevant Diseases	Trial Status	Ref.
Caspases	Caspase		Multiple malignancies	Preclinical	39-40
	activator			(in vitro)
Bcl-2 family	Bcl-2 antisense	Genasense	Non-Hodgkin’s	Phase III, Phase I	52-55
			lymphoma, leukemia,	with
			melanoma, and small cell lung carcinoma	chemotherapy
	Small molecule	BH3I-1, BH3I-2		Preclinical	58
	inhibitor of			(in vivo)
	Bcl-xL BH3 binding Small molecule	Antimycin A		Preclinical	59
	inhibitor of			(in vivo)
	Bcl-2 BH3 binding Natural	Chelerythrine		Preclinical	61
	inhibitor of			(in vitro)
	Bcl-xL BH3
	binding
p53	p53 gene	INGN201,	Head and neck cancer,	Clinical trials,	83-86
	replacement	SCH58500,	ovarian cancer	approved
		Gendicine		(China)
	Oncolytic virus	ONYX-015	Head and neck cancer,	Phase II, Phase I	88-89
			oral dysplasia
	p53 C-terminus	TAT-p53C	Peritoneal lymphoma	Preclinical	95
	peptide			(in vivo)
	Rescue of	CP-31398		Preclinical	90-92
	mutant p53 conformation/ function			(in vivo)
	Restoration of	Prima 1		Preclinical	78, 93
	mutant p53 function			(in vivo)
	Disruption of	Nutlins		Preclinical	104
	p53-MDM2 interaction			(in vivo)
	Disruption of	MDM2 antisense	Colon cancer, prostate	Clinical trials	101-103
	MDM2		cancer, and lymphoid
			cancers
Survival kinase	H-ras antisense	ISIS 2503	Advanced carcinoma	Phase I	113
pathways	HER2	Herceptin	Breast cancer	Approved	114, 115
	monoclonal antibody Inhibitor of Bcr-	Imatinib mesylate	CML, gastrointestinal	Approved	116-118
	Abl, c-KIT, PDGFR	(Gleevec)	stromal tumors
	EGFR inhibitor	Iressa	Non-small cell lung	Approved	119

carcinoma

TABLE 27.1 (Continued) Strategies to Induce Cell Death

bgcolor=white>Melanoma

Category	Target/Strategy	D^rug	Examples of Relevant Diseases	Trial Status	Ref.
	mTOR	RAD001,	Breast, pancreatic,	Phase II, Phase	123
	inhibitors	CC1779	brain, and renal	III
			cancers
	BRAF inhibitor	BAY-43-9006	Phase III	127
	RAF antisense	ISIS 5132	NSCLC, prostate	Phase II	128
			cancer
	IKK inhibitor	Various	Hematologic	Preclinical	135
			malignancies
	E1A expression	Tg-DCC-E1A	Breast, ovarian, head,	Phase I, Phase II	145
	to inhibit multiple kinases		and neck cancers
Proteasome	26S proteasome	PS-341	Hematologic	Clinical trials	159
	inhibitor		malignancies
Gene silencing	DNA	Decitabine, 5-	Hematologic	Phase II, Phase	164, 165
	methylation inhibitor	azacytidine	malignancies	III
	HDAC inhibitor	Depsipeptide	Hematologic		166, 167
			malignancies
ROS	Photodynamic therapy	Porphyrin, chlorin	Solid tumors	Phase II	204

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Source: Badley A.D. (ed.). Cell Death During HIV Infection. Taylor & Francis,2006. — 511 p.. 2006

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