Shifting the cancer paradigm: must we kill to cure?

Schipper, Harvey; Goh, C.; Wang, T L

doi:10.1200/jco.1995.13.4.801

Cited by 67 publications

(30 citation statements)

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“…E-mail: MD49@MUSICA.MCGILL.CA. Dr. Pollak's-laboratory research is funded by the National Cancer Institute of Canada aualitv of life resulting from the temporary decrease in tU-research regarding innovative noncytotoxic approaches to cancer treatment (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Antineoplastic Action of Somatostatin Analogs

Pollak

Schally

1998

Experimental Biology and Medicine

152

126

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Abstract. Over the past decade, impressive antineoplastic activity of somatostatin analogs has been demonstrated in many tumor models. More recent research has provided information regarding mechanisms underlying the antiproliferative and apoptosis-inducing actions of these compounds. These include both 'direct' mechanisms that are sequellae of binding of somatostatin analogs to somatostatin receptors present on neoplastic cells and 'indirect' mechanisms related to effects of somatostatin analogs on the host. The upregulation of intracellular tyrosine phosphatase activity triggered by binding of ligands to the type II somatostatin receptor has received considerable attention as a direct mechanism, not only because this activity is the converse of the tyrosine kinase activity associated with many peptide mitogen receptors, but also because the type II somatostatin receptor is frequently expressed by common human neoplasms, including breast cancer. The potential importance of indirect mechanisms of action of somatostatin analogs, such as alterations in host insulin-like growth factor physiology, is emphasized by the in vivo antineoplastic activity of these compounds against somatostatin receptor-negative neoplasms. Clinical efficacy and a favorable toxicity profile of somatostatin analogs in the treatment of relatively uncommon conditions such as acromegaly and neuroendocrine tumors have already been demonstrated. Preclinical data now are sufficient to justify controlled clinical trials in breast, prostate, and pancreatic cancer. The development of monthly depot formulations will facilitate the clinical evaluation of somatostatin analogs for these and other indications.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of Antineoplastic Action of Somatostatin Analogs

Pollak

Schally

1998

Experimental Biology and Medicine

152

126

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“…However, the realistic goal in clinical oncology is to improve survival and quality of life and prevent recurrent disease. 82 Rigorous criteria are required for animal models to predict clinical efficacy. This contrasts with the convenient tumor models 5 that often use repeated measures of tumor burden as the easiest measure of efficacy.…”

Section: Outcome Criteria For Animal Tumor Modelsmentioning

confidence: 99%

Murine Models to Evaluate Novel and Conventional Therapeutic Strategies for Cancer

Talmadge

Singh

Fidler

et al. 2007

The American Journal of Pathology

417

330

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Animal models, by definition, are an approximation of reality, and their use in developing anti-cancer drugs is controversial. Positive retrospective clinical correlations have been identified with several animal models, in addition to limitations and a need for improvement. Model inadequacies include experimental designs that do not incorporate biological concepts, drug pharmacology, or toxicity. Ascites models have been found to identify drugs active against rapidly dividing tumors; however, neither ascitic nor transplantable subcutaneous tumors are predictive of activity for solid tumors. In contrast, primary human tumor xenografts have identified responsive tumor histiotypes if relevant pharmacodynamic and toxicological parameters were considered. Murine toxicology studies are also fundamental because they identify safe starting doses for phase I protocols. We recommend that future studies incorporate orthotopic and spontaneous metastasis models (syngeneic and xenogenic) because they incorporate microenvironmental interactions, in addition to confirmatory autochthonous models and/or genetically engineered models, for molecular therapeutics. Collectively, murine models are critical in drug development, but require a rational and hierarchical approach beginning with toxicology and pharmacology studies, progressing to human primary tumors to identify therapeutic targets and models of metastatic disease from resected orthotopic, primary tumors to compare drugs using rigorous, clinically relevant outcome parameters. Animal models are critical for the development of novel therapeutics; however, we have been minimally successful in decreasing the age-adjusted death rate for cancer compared with cardiac disease. In 2003, for the first time since 1930 when epidemiological records were initiated, fewer people (Ͻ85 years old) died of cardiac disease as compared with cancer.1 This historic change was attributable to a 60, 70, and 0% decrease in mortality by heart disease, stroke, and cancer, respectively. Thus, it is warranted to review the approaches and tumor models used in the identification and development of new anti-cancer therapeutics. Tumor initiation, progression, and metastasis is a complex, multifactorial process that selects tumor variants from a heterogeneous primary tumor.2,3 Therapeutic intervention is also a selective pressure that can result in tumor cell populations refractory to specific drugs.4 Therefore, to model and study tumor biology and drug activity, the selection of clinically relevant animal and tumor models is critical.Originally, drug screens used leukemic cell lines that, when injected intraperitoneally (i.p.) resulted in tumor ascites. These tumor models were successful in identifying active therapeutics against leukemias and some lymphomas; however, they were inadequate for the identification of therapeutics against solid tumors. 5-7

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“…This possibility finds support in reports of leukemia-associated fusion transcripts in normal hematopoietic cells. 36,[62][63][64] If, on the other hand, other physiologic mechanisms are to be held responsible for this symbiosis, 65 and these cells have the genetic make-up to potentially cause relapse, then these few cells truly represent MRD with potential therapeutic consequences.…”

Section: Curementioning

confidence: 99%

Assessing minimal residual disease (MRD) in leukemia: a changing definition and concept?

Paietta

2002

Bone Marrow Transplant

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Shifting the cancer paradigm: must we kill to cure?

Cited by 67 publications

References 0 publications

Mechanisms of Antineoplastic Action of Somatostatin Analogs

Mechanisms of Antineoplastic Action of Somatostatin Analogs

Murine Models to Evaluate Novel and Conventional Therapeutic Strategies for Cancer

Assessing minimal residual disease (MRD) in leukemia: a changing definition and concept?

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