Numerous experimental, epidemiologic, and clinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the highly selective cyclooxygenase (COX)-2 inhibitors, have promise as anticancer agents. NSAIDs restore normal apoptosis in human adenomatous colorectal polyps and in various cancer cell lines that have lost adenomatous polyposis coli gene function. NSAIDs also inhibit angiogenesis in cell culture and rodent models of angiogenesis. Many epidemiologic studies have found that long-term use of NSAIDs is associated with a lower risk of colorectal cancer, adenomatous polyps, and, to some extent, other cancers. Two NSAIDs, sulindac and celecoxib, have been found to inhibit the growth of adenomatous polyps and cause regression of existing polyps in randomized trials of patients with familial adenomatous polyposis (FAP). However, unresolved questions about the safety, efficacy, optimal treatment regimen, and mechanism of action of NSAIDs currently limit their clinical application to the prevention of polyposis in FAP patients. Moreover, the development of safe and effective drugs for chemoprevention is complicated by the potential of even rare, serious toxicity to offset the benefit of treatment, particularly when the drug is administered to healthy people who have low annual risk of developing the disease for which treatment is intended. This review considers generic approaches to improve the balance between benefits and risks associated with the use of NSAIDs in chemoprevention. We critically examine the published experimental, clinical, and epidemiologic literature on NSAIDs and cancer, especially that regarding colorectal cancer, and identify strategies to overcome the various logistic and scientific barriers that impede clinical trials of NSAIDs for cancer prevention. Finally, we suggest research opportunities that may help to accelerate the future clinical application of NSAIDs for cancer prevention or treatment.

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Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues

A 44 amino acid peptide with growth hormone-releasing activity has been isolated from a human tumor of the pancreas that had caused acromegaly. The primary structure of the tumor-derived peptide is H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser- Ala- Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Ar g-Gly -Ala-Arg-Ala-Arg-Leu-NH2. The synthetic replicate has full biological activity in vitro and in vivo specifically to stimulate the secretion of immunoreactive growth hormone. The tumor-derived peptide is identical in biological activity and similar in physiochemical properties to the still uncharacterized growth hormone-releasing factor present in extracts of hypothalamic tissues.

https://science.sciencemag.org/content/sci/218/4572/585.full.pdf

Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly.

Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta-gonad-mesonephros region subsequently colonize fetal and adult haematopoietic organs. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.

Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

The neuroregulation of growth hormone (GH) secretion is mediated in part by a stimulatory, GH-releasing factor (GRF) and an inhibitory peptide, somatostatin1, both of which reach the adenohypophysis by the hypothalamic-hypophysial portal system2. Somatostatin has been shown to be a tetradecapeptide3,4, a large form of which was later also sequenced5. The existence of a GRF is supported by physiological evidence6–9 and by reports of GH-releasing activity in hypothalamic extracts10–17. Although several agents with GH-releasing activity have been identified14–16, none is of high potency and fulfils the criteria expected of a physiological GRF18,19. GH-releasing activity observed in extracts of carcinoid and pancreatic islet tumours removed from patients with GH hypersecretion, acromegaly and pituitary adenoma or hyperplasia has been partially characterized20–23. We report here the sequence of a 40 residue GH-releasing peptide purified from a pancreatic islet tumour described earlier by Thorner et al.23. A synthetic replicate of this peptide, termed human pancreatic tumour GRF [hpGRF(1–40)]-OH, co-elutes on HPLC with the native peptide and is highly potent in stimulating GH secretion in vitro and in vivo. A close structural homology with the peptides of the glucagon–secretin family, and more particularly with PHI24, is recognized. Structure–activity studies show that hpGRF(1–29)-NH2 has full intrinsic activity and potency in vitro.

Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour.

This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system.

Pharmacological and Clinical Aspects of Heme Oxygenase

Antibodies to prostaglandin were obtained by immunization of rabbits with PGA(1), PGA(2), and PGE(1), protein conjugates of prostaglandins. The antibodies demonstrated specificity toward both the cyclopentane ring and the aliphatic side chains. With the use of these antibodies a highly sensitive radio-immunoassay capable of measuring less than picomolar amounts of PGA1, PGA2, and PGE1 has been developed.

https://science.sciencemag.org/content/sci/171/3970/494.full.pdf

Radioimmunoassay for prostaglandins.

Prostaglandins and cancer: An update

PROSTAGLANDIN E (PGE), both endogenous and exogenous, has been shown to inhibit significantly the rates of tumour-cell proliferation in vitro1–4 .Suppression of PG biosynthesis with indomethacin5,6 resulted in stimulation of cell replication, an effect which was readily reversed by the addition to the medium of small amounts of exogenous PGE1 (10 ng ml−1) (ref. 5). Corticosteroids have recently been shown to inhibit the biosynthesis of PGE by rheumatoid synovia7 and mouse fibro-sarcoma HSDM1 (ref. 8) in vitro; the mechanism of this action seems to be by interfering with the release of arachidonic acid from phospholipids9. To evaluate further the possible role of PGE in the control of tumour-cell proliferation, we have studied the effects of hydrocortisone and indomethacin on the growth rate of B-16 mouse melanoma in vitro. The studies demonstrate that both compounds cause significant stimulation of tumour-cell replication in vitro, associated with inhibition of PG biosynthesis, albeit by two different mechanisms. In addition, we have extended the observations on the effects of exogenous PGE1, by demonstrating that subcutaneous administration of 16,16-dimethyl-PGE2-methyl ester significantly inhibits tumour growth in vivo.

Bernard M. Jaffe

Papers

Radioimmunoassay for prostaglandins.

Prostaglandins and cancer: An update

Inhibition of tumour growth in vivo and in vitro by prostaglandin E

The relationship between concentration of prostaglandin E and rates of cell replication

Validation and application of a radioimmunoassay for serotonin.