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BRIEF PROPOSAL CHROMOSOMAL RESIDUAL PROTEIN-SH GROUPS IN CANCER AND GENE CONTROL FRANCES E. KNOCK, Ph.D., M.D* Dr. Szent-Györgyi and co-workers recently found that sulfhydryl (SH) inhibitors, such as pyruvaldehyde, preferentially inhibit cell division ofa variety oflower forms with less effect on normal cells than cancer [1,2]. Retine, which probably contains pyruvaldehyde (methyl glyoxal) as active component, has been found from mushrooms to clams to humanurine, andmay act as aratheruniversal cell regulator. Együdand Szent-Györgyi predicted that proper SH inhibition may open the way to a specific cancer therapy [2]. Since 1963, sensitivity tests on hundreds of human carcinomas, sarcomas, and lymphomas have shown greater attack on human cancers than normal tissues by SH inhibitors like oxophenarsine (3-amino-4-hydroxyarsenosobenzene) and pyruvaldehyde [3-5]. The sensitivity tests have agreed with statistically significant assays of drug effects against animal cancers for a wide variety ofdrugs, both active and inactive, and have predicted results ofclinical cancer chemotherapy with SH inhibitors and other drugs. Histochemically , pyruvaldehyde and other active SH inhibitors are seen to react with nuclear proteinSH groups of human cancers regressed by SH inhibitors [5]. Available clinical data suggest that some sulfhydryl inhibitors can cause regression in a variety ofhuman cancers without injury to rapidly dividing normal cells of bone marrow and wounds. The SH inhibitor potassium arsenite now is mainly ofhistoric interest, but in myelogenous leukemia temporarily can effect rise in hemoglobin while leukemic leukocyte counts fall and size of liver and spleen decrease. The SH inhibitor iodoacetate with adjuncts malonate and fluoride has effected objective regression of a variety of leukemias and solid tumors, apparently without injury to normal blood cells [6]. Patients in whom solid tumors were regressed showed no morphologic change in blood components at the same dose of SH inhibitor which destroyed blast cells in leukemic patients. The SH inhibitor ethylene bis iodoacetate caused impressive tumor regression in only a small percentage ofpatients, but its lack of injury to hematopoietic activity in patients undergoing recent surgery, radiation, and chemotherapy with alkylating agents has been noted [7]. * Presbyterian-St. Luke's Hospital, Chicago, Illinois 60612, and Veterans Administration Hospital , Hines, Illinois 6014t. 310 Frances E. Knock · BriefProposal Perspectives in Biology and Medicine · Winter 1967 In sensitivity tests against a wide spectrum ofhuman cancers, activity ofSH inhibitors oxophenarsine and 2-(N4-acetylsulfanilamido)ethyl iodoacetate has surpassed that of arsenite, iodoacetate, or ethylene bis iodoacetate, alone and with adjuncts. Clinically, oxophenarsine and 2-(N4-acetylsulfanilamido)ethyl iodoacetate plus adjuncts malonate, heparin, and fluoride have regressed a variety ofcarcinomas, sarcomas, and lymphomas without injury to normal wound healing or hematologic status, or with actual improvement inhematologic status ofthe patients even when used immediately after major cancer surgery [8]. Patients with leukocyte counts as low as 1,200 per cubic millimeter and platelet counts as low as 11,000 per cubic millimeter have shown improvement in hematologic status during treatment with the SH inhibitors. The main clinical target of the sulfhydryl inhibitors is chromosomal residual protein, which contains SH groups and an excess ofacidic over basic groups [9] by contrast with histones. Histones probably lack the specificity and chemical sensitivity needed for gene control and are not associated with DNA in bacteria where complex gene regulation occurs. Zalokar has pointed out that histones probably keep genes incompetent, that removal of histones probably makes genes susceptible to the action of inducers but does not make genes active [10]. Thus, histones appear to be the brakes ofthe cellular mechanism whose accelerator and steering mechanisms still elude us. The apparently preferential attack of SH inhibitors like oxophenarsine and Retine on human cancers [1, 3, 5, 8] and cell division, the apparent universality of the SHinhibiting Retine as a potential cell regulator [1, 2], and the marked susceptibility of SH to most known carcinogens suggest that the main clinical target ofthe SH inhibitors, the SH-bearing chromosomal residual protein, may play a major role in regulating DNA. The SH-bearing residual protein is present on competent DNA where histones are deficient and the main synthesis of RNA probably occurs; SH-bearing residual protein increases in normal growth and cancer, is appropriately sensitive to anticancer agents [3...

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