High-dose cimetidine for the treatment of metastatic renal cell carcinoma. A Hoosier Oncology Group study.

The Hoosier Oncology Group evaluated cimetidine in 42 patients with metastatic renal cell carcinoma. There were two complete remissions that lasted for 26 and 33+ months in 38 evaluable patients. There were no partial remissions. Toxicity was minimal. Patients with renal cell carcinoma can occasionally respond to cimetidine with long-term remission.

A RAS oncogene imparts growth factor independence to myeloid cells that abnormally regulate protein kinase C: a nonautocrine transformation pathway.

The factor-dependent cell line FDC-P1 has been utilized as a model of interleukin 3 (IL-3)-dependent myeloid cell proliferation. However, it has been recently observed that active phorbol esters (e.g., phorbol 12-myristate 13-acetate) may entirely replace IL-3 to promote its proliferation. These observations reveal abnormal regulation of protein kinase C (pkC) (absence of downregulation or overexpression). This property allowed a test of the hypothesis that the T24 RAS (codon 12) oncogene acts by constitutive and persistent pkC activation, driving proliferation. FDC-P1 cells were transfected by electroporation with the T24 RAS-containing vector pAL 8, or with a control vector pSVX Zip Neo, and neomycin-resistant clones were selected. Multiple RAS-transfectant clones were categorized for their growth factor requirement and incorporation of the 6.6-kb human mutant H-RAS genome. IL-3-independent clones had incorporated multiple (more than two) copies of the entire 6.6-kb RAS genome. The incorporation of multiple 6.6-kb RAS genomes was correlated with high-level p21 RAS expression. No evidence for autostimulatory growth factor production by clones containing the RAS oncogene was observed. Thus, acquisition of growth factor independence in myeloid cells by abundant expression of a RAS oncogene is linked, in part, to abnormal regulation of pkC, which acts as a collaborating oncogene.

Restoration of adenylate cyclase responsiveness in murine myeloid leukemia permits inhibition of proliferation by hormone. Butyrate augments catalytic activity of adenylate cyclase.

Mechanisms of leukemic cell clonal dominance may include aberrations of transmembrane signaling. In particular, neoplastic transformation has been associated with reduced capacity for hormone-stimulated adenylate cyclase activity. In the present study, prostaglandin E, a hormonal activator of adenylate cyclase that has antiproliferative activity in myeloid cells, and cholera toxin, an adenylate cyclase agonist that functions at a postreceptor site by activating the adenylate cyclase stimulatory GTP-binding protein (Gs), were studied for antiproliferative activity in two murine myeloid cell lines. FDC-P1, an interleukin 3 (IL 3)-dependent myeloid cell line and a tumorigenic IL 3-independent subline, FI, were resistant to these antiproliferative agents. The in vitro ability of the "differentiation" agent, sodium butyrate, to reverse their resistance to adenylate cyclase agonists was studied. The antiproliferative action of butyrate involved augmentation of transmembrane adenylate cyclase activity. Increased adenylate cyclase catalyst activity was the primary alteration of this transmembrane signaling group leading to the functional inhibitory effects on leukemia cells, although alterations in regulatory G-proteins appear to play a secondary role.

Cellular control of in vitro progression of murine myeloid leukemia: progression accompanies acquisition of independence from growth factor and stromal cells.

The ability of bone marrow stroma cells of normal WCB6F1 (+/+) mice versus their congenic Sl/Sld stromal-defective littermates to support sustained proliferation and leukemic transformation of the growth factor-dependent myeloid cell line FDC-P1 was studied. Extensive proliferation of factor-dependent cells occurred on (+/+) normal long-term marrow culture stroma without the addition of growth factor, whereas factor-dependent cells dissipated from Sl/Sld stromal cultures after addition. The sustained proliferation that occurred on +/+ stromal layers later resulted in the appearance of factor-independent cell lines that were no longer dependent upon stroma. Factor-independent cell lines were cloned by limiting dilution and analyzed for expression of cell surface antigens to prove their origin from FDC-P1. Factor-independent cells, but not factor-dependent cells, formed tumors in syngeneic mice. These studies demonstrate a critical role for marrow stroma in the stepwise development of murine leukemia and are concordant with the previous data obtained in in vivo studies by McCool et al. that the splenic stroma of irradiated Sl/Sld mice do not support growth of Friend virus-induced preleukemic cell colonies. The present data demonstrate in a preleukemia model not induced by Friend virus complex that normal (+/+) stromal cells promote the in vitro proliferation of factor-dependent preleukemic cells and their subsequent transition to factor-independent leukemia cells, but Sl/Sld defective stroma do not efficiently promote this transition.

Studies with 17 beta(16 alpha-[125i]iodo)-estradiol, an estrogen receptor-binding radiopharmaceutical, in rats bearing mammary tumors.

We have studied the distribution of 17 beta(16 alpha-[125I]iodo)-estradiol (I-E2) in tumor-bearing and normal rats. High early adrenal-to-blood ratios (up to 22 at 5 min) were seen in all groups, but this fell to six at 1 hr. Uterus-to-blood ratios of 15 were found, and these were fairly constant up to 2 hr after administration. Uptake of label in the uterus, but not in the adrenals, was sensitive to excess diethylstilbestrol, which competes with I-E2 for estrogen receptors. Mean tumor-to-blood ratios of 1.4, 5.5, and 8.7 were seen at 1 hr in rats with transplanted, spontaneous, and N-nitrosomethylurea-induced tumors, respectively. Diethylstilbestrol was shown to reduce uptake of label by spontaneous tumors. Most of the radioactivity was excreted in the bile by 1 hr. Better estrogen-receptor-binding radiopharmaceuticals can probably be designed.