Systemic cancer therapy: Evolution over the last 60 years

Dy, Grace K.; Adjei, Alex A.

doi:10.1002/cncr.23651

Cited by 44 publications

(44 citation statements)

References 223 publications

(191 reference statements)

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“…Classical genotoxic chemotherapeutic agents cause intrinsic apoptosis by inducing extreme stress to the DNA and its repair mechanisms, and are also toxic to noncancerous cells (11). Development of targeted therapeutics led to increased selectivity, but these options are often effective against only a small subset of cancers.…”

Section: Introductionmentioning

confidence: 99%

Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts

Griffin

Karnik

McNulty

et al. 2011

Molecular Cancer Therapeutics

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The naturally occurring Amaryllidaceae alkaloid pancratistatin exhibits potent apoptotic activity against a large panel of cancer cells lines and has an insignificant effect on noncancerous cell lines, although with an elusive cellular target. Many current chemotherapeutics induce apoptosis via genotoxic mechanisms and thus have low selectivity. The observed selectivity of pancratistatin for cancer cells promoted us to consider the hypothesis that this alkaloid targets cancer cell mitochondria rather than DNA or its replicative machinery. In this study, we report that pancratistatin decreased mitochondrial membrane potential and induced apoptotic nuclear morphology in p53-mutant (HT-29) and wild-type p53 (HCT116) colorectal carcinoma cell lines, but not in noncancerous colon fibroblast (CCD-18Co) cells. Interestingly, pancratistatin was found to be ineffective against mtDNA-depleted (r 0 ) cancer cells. Moreover, pancratistatin induced cell death in a manner independent of Bax and caspase activation, and did not alter b-tubulin polymerization rate nor cause double-stranded DNA breaks. For the first time we report the efficacy of pancratistatin in vivo against human colorectal adenocarcinoma xenografts. Intratumor administration of pancratistatin (3 mg/kg) caused significant reduction in the growth of subcutaneous HT-29 tumors in Nu/Nu mice (n ¼ 6), with no apparent toxicity to the liver or kidneys as indicated by histopathologic analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Altogether, this work suggests that pancratistatin may be a novel mitochondria-targeting compound that selectively induces apoptosis in cancer cells and significantly reduces tumor growth.

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Section: Introductionmentioning

confidence: 99%

Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts

Griffin

Karnik

McNulty

et al. 2011

Molecular Cancer Therapeutics

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“…As monotherapy is poorly effective, chemotherapeutic drugs are combined in polychemotherapy protocols to increase anti-tumor efficiency. [1][2][3] Combinations of different chemotherapeutic drugs have been optimized heuristically in clinical multicenter trials. Because of substantial efforts required to realize clinical trials, only a limited number of drug combinations and application parameters could be optimized clinically.…”

Section: Introductionmentioning

confidence: 99%

Optimized anti–tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule

Ehrhardt¹,

Schrembs

Moritz

et al. 2011

Blood

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“…• Antisense Oligonucleotides (ASOs) TGF-β antisense oligonucleotides (ASO) as single strands of RNA (13 -25 nucleotides in length) that are complementary to a chosen sequence of TGF-β mRNA. They prevent TGF-β protein translation of TGF-β mRNA strands through complementary nucleic acid hybridization and accelerated mRNA degradation by RNase H. In general, because multiple copies of a protein are produced by each mRNA molecule, targeting mRNA rather than the protein itself is potentially a more efficient approach to modulate protein function by altering its levels [36]. ASOs have some limitations which need to be taken into account when using them.…”

Section: • Ligand Trapsmentioning

confidence: 99%

Targeting Transforming Growth Factor-<i>β</i> (TGF-<i>β</i>) in Cancer and Non-Neoplastic Diseases

Nacif¹,

Shaker²

2014

JCT

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Transforming growth factor-β (TGF-β) superfamily is a key player in the regulation of a wide variety of physiological processes from development to pathogenesis. Since the discovery of the prototypic member, TGF-β, almost three decades ago, there have been tremendous advances in our understanding of its complex biology. TGF-β misregulation has been implicated in the pathogenesis of a variety of diseases, including cancer with a direct role in facilitating metastasis, fibrosis and inflammation. Consequently, TGF-β is currently explored as a prognostic candidate biomarker of tumor invasiveness and metastasis; and it offers an attractive target for cancer therapy. Several anti-TGF-β approaches, such as TGF-β antibodies, antisense oligonucleotides and small molecules inhibitors of TGF-β type 1 receptor kinase, have shown great promise in the preclinical studies. Here, we consider why the TGF-β signaling pathway is a drug target, the potential clinical applications of TGF-β inhibition, the issues arising with anti-TGF-β therapy and how these might be adopted using personalized approaches with a special care for patient selection and timing of therapy so that we may bring forward all the potentials of targeting this pathway for therapeutic uses in both cancer, preferentially in combination therapy, and non-neoplastic diseases.

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Systemic cancer therapy: Evolution over the last 60 years

Abstract: The 1940s marked the beginning of an era of important discoveries that contributed to modern concepts underlying the current practice of cancer chemotherapy, such as the log kill hypothesis reported by Skipper, the Norton-Simon

Cited by 44 publications

References 223 publications

Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts

Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts

Optimized anti–tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule

Targeting Transforming Growth Factor-<i>β</i> (TGF-<i>β</i>) in Cancer and Non-Neoplastic Diseases

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Systemic cancer therapy: Evolution over the last 60 years

Abstract: The 1940s marked the beginning of an era of important discoveries that contributed to modern concepts underlying the current practice of cancer chemotherapy, such as the log kill hypothesis reported by Skipper, the Norton-Simon

Cited by 44 publications

References 223 publications

Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts

Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts

Optimized anti–tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule

Targeting Transforming Growth Factor-&lt;i&gt;β&lt;/i&gt; (TGF-&lt;i&gt;β&lt;/i&gt;) in Cancer and Non-Neoplastic Diseases

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Targeting Transforming Growth Factor-<i>β</i> (TGF-<i>β</i>) in Cancer and Non-Neoplastic Diseases