Ribonucleases as a Novel Pro-Apoptotic Anticancer Strategy: Review of the Preclinical and Clinical Data for Ranpirnase

Abstract

Cytotoxic ribonucleases (RNases), such as ranpiranase, represent a novel mechanism-based approach to anticancer therapy. These relatively small proteins selectively attack malignant cells, triggering apoptotic response and inhibiting protein synthesis. Ranpirnase, originally isolated from oocytes of Rana pipiens, is a member of a family of endoribonucleases. The anticancer effects of ranpiranase have been documented in both in vitro and in vivo experimental tumor models. The effects of ranpiranase appear to be selective for cancer cells. Based on Phase I study data, the maximum tolerated dose (MTD) was 960 microg/m2, with the dose-limiting toxicity (DLT) characterized by proteinuria with or without azotemia, peripheral edema, and fatigue. Ranpirnase did not induce myelosuppression, mucositis, alopecia, cardiotoxicity, coagulopathy, hepatotoxicity, or adverse metabolic effects. Phase II tumor-specific trials investigated the activity of ranpirnase in malignant mesothelioma, breast cancer, non-small cell lung cancer, and renal cell cancer. A Phase III randomized study in malignant mesothelioma patients compares the combination of ranpirnase plus doxorubicin to doxorubicin monotherapy.

TNF-α inhibits asbestos-induced cytotoxicity via a NF-κB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis

“…In addition, blocking TNF-␣ may lead to novel preventive strategies for MM. Examples might include blocking TNF-␣ with etanercept (Enbrel), a recombinant decoy receptor for TNF-␣ that is under investigation in breast cancer patients (44) or disruption of the NF-B pathway, for example with Onconase (Ranpirnase), a drug that inhibits the NF-B pathway (45) and that has already shown favorable effects in some MM patients (46).…”

Evolution and Function of Leukocyte RNase A Ribonucleases of the Avian Species, Gallus gallus

“…We have re-isolated full-length cDNAs of the two chicken leukocyte RNases by reverse transcription-PCR from RNA prepared from the bone marrow of White Leghorn chickens (G. gallus) and have deposited sequences into GenBank TM as chicken leukocyte RNase A-1 (DQ395275) and chicken leukocyte RNase A-2 (DQ395276). These sequences share 93% nucleotide sequence identity to one another and are identical to RNase A/angiogenin (19) and RSFR (20) Rabbit antibodies prepared against divergent peptides shown in Fig. 2A (anti-A-1, NH 2 -QPNRALRTTQQQLP-COOH; anti-A-2, NH 2 -DQALRRTRRHFRIT-COOH) were evaluated for activity and specificity by immunoblotting against recombinant carboxyl-terminal FLAG-tagged recombinant leukocyte RNase A-1 and A-2 (Fig.…”

“…Several RNase A ribonucleases of the frog genus Rana have been isolated (15)(16)(17)(18), including the cancer biotherapeutic agent, onconase (19). Also characterized are several RNase A ribonucleases from birds (14, 20 -22) and reptiles (23)(24)(25).…”

Ribonuclease binase inhibits primary tumor growth and metastases via apoptosis induction in tumor cells

“…[1][2][3][4][5] The antitumor activity was shown for BS-RNase from bovine seminal, [6][7][8][9] onconase from oocytes of Rana pipiens, [10][11][12] bovine pancreatic RNase A, 13 cSBL and jSBL RNases from Rana catesbeiana and Rana japonica, 14 microbial RNases [15][16][17] and conjugates of RNases with various molecules. [18][19][20] One of the properties that are important for potential therapeutic application of RNases is their ability to induce cancer cell death by apoptosis.…”