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.

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The differentiation potential of the Lucké renal carcinoma of the northern leopard frog, Rana pipiens, can be characterized by the nuclear transplantation procedure. Transplantation of tumor nuclei into activated and enucleated ova results, in the best of cases, in swimming larvae which fail to feed. The larvae die in about 10 to 14 days. Rescue of tumor nuclear transplantation tadpole tissue, destined to die, has been accomplished by allografting fragments of that tissue to normal hosts. The allografts persist and differentiate a diversity of tissues which cannot be distinguished by histological analysis from allografted normal control tissue. Allografts are an imperfect mode of assay for histological competence because of the immune response of the host. Lymphocytes and eosinophils invade the grafts in about 40 days. The host immune response occurs in both experimental and control allografts. Consequently, we believe that added histogenetic potential exists in the genome of the Lucké renal carcinoma. We propose that unexpressed differentiative potential of the grafted tissue can be extracted by abrogation of the immune response of the host. A herpesvirus is the etiological agent of the Lucké renal carcinoma. We currently seek to detect viral DNA in tissue derived from tumor nuclear transplant embryos. The presence of the viral genetic material in normal mitotic progeny of Lucké tumor cells, if demonstrated, raises the question of the long-term stability of differentiated cells derived from a virus tumor. Alternatively, absence of viral DNA in the tumor nuclear transplant tissue would suggest that normal differentiation ensues after elimination of the oncogenic DNA from that tissue. Loss of viral DNA may prognosticate stable differentiation.

The acute effects of Pb++, Cd++ and Hg++ have been studied on the amphibian neuromuscular junction. These heavy metal ions primarily affect those presynaptic mechanisms which underlie neurotransmitter release; no significant postsynaptic effects were observed. All experiments were performed on the isolated sciatic nerve/sartorius muscle preparation. Conventional electrophysiological techniques using intracellular recordings were used to monitor acetylcholine (ACh) release. Ringer solutions usually contained high Mg++ and low Ca++ concentrations so that endplate potentials (EPPs) could be recorded under contraction-free conditions. Pb++, Cd++ and Hg++ were added to the Ringer solutions as chloride salts. Of the two forms of transmitter release, Pb++ blocked one (evoked release or EPP amplitude) and stimulated the other (the rate of spontaneous release or MEPP frequency). When a preparation was first exposed to a moderate dose of Pb++, the EPP amplitude decreased within about 1-2 min; however, at that time, the MEPP frequency was just beginning to increase. Low concentrations of Pb++ often reduced the EPP greatly without altering the MEPP frequency. Evidence is provided for a competitive interaction between Pb++ and Ca++ ions in evoked release which is believed to occur on the extracellular side of the nerve terminal. The dissociation constant between Pb++ and the presynaptic Ca++ receptor is about 1 microM. The increase in MEPP frequency is assumed to be due to an intracellular action of Pb++ which may reduce the ability of nerve terminal organelles to sequester Ca++ and thereby increase the intracellular concentration of ionized Ca++. Cd++ also blocks evoked ACh release by a competitive inhibitory mechanism similar to that for Pb++. Cd++ is slightly less potent than Pb++, the dissociation constant for Cd++ being around 2.8 microM. In contrast to Pb++, Cd++ does not increase resting MEPP frequency. Hg++ is unique in that it first causes an increase in evoked ACh release and then a sudden and complete blockade; the MEPP frequency follows a similar time course. The mechanism underlying these effects of Hg++ is uncertain.

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