Cancer research
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Studies were designed to determine whether salivary gland extract (SGE) from the leech Haementeria officinalis could inhibit enhancement of lung tumor colonization induced by pretreatment of mice with cyclophosphamide (CY) or local thoracic irradiation (LTI). Tumor nodules in the lung were generated by i.v. injections of T241 sarcoma and FSA fibrosarcoma cells into syngeneic C57BL/6 and C3Hf/Kam mice, respectively. CY (200 mg/kg) was given i.p. 1 or 4 days prior to i.v. injection of tumor cells. ⋯ Using [125I]iododeoxyuridine-labeled tumor cells, it was observed that SGE did not affect the initial lodgement of tumor cells in the lung, but it greatly facilitated their subsequent release from the lung. In normal mice, the SGE was active when given on the day or 1 day before but not when given 4 days before tumor cells. The antimetastatic effect of SGE was ascribed to its anti-platelet-aggregating, anticoagulant, and antiproteolytic enzyme activities.
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9-beta-D-Arabinofuranosyl-2-fluoroadenine (2-F-ara-A) and 2-fluoro-2'-deoxyadenosine (2-FdAdo) were potent inhibitors of L1210 cell growth in culture. Even though these 2-fluoroadenine nucleosides are very poor substrates for adenosine deaminase, erythro-9-(2-hydroxyl-3-nonyl)adenine potentiated the growth-inhibitory properties of 2-FdAdo but not 2-F-ara-A in a synergistic manner. 2-FdAdo and 2-F-ara-A inhibited the conversion of [3H]cytidine to deoxycytidine nucleotides and incorporation into DNA, suggesting that ribonucleotide reductase was an intracellular site of action. 2-F-ara-A (6 microM) in combination with 2,3-dihydro-1H-pyrazole[2,3-a]imidazole gave synergistic inhibition of L1210 cell growth. At lower concentrations of 2-F-ara-A, the inhibition by this combination was only additive. ⋯ Similar results were obtained with combinations which included F-ara-A, hydroxyurea, and Desferal. The combinations of 2-FdAdo plus 2,3-dihydro-1H-pyrazole[2,3-a]imidazole or hydroxyurea gave strong synergistic inhibition of L1210 cell growth, even at the lowest concentration of 2-FdAdo (0.6 microM) studied. The presence of Desferal in the combination served to further potentiate the synergism.
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Pokeweed antiviral protein (PAP) and ricin A chain are potent inhibitors of protein synthesis that inactivate eukaryotic 60S ribosomal subunits. Immunotoxins were prepared by linking monoclonal anti-Thy 1.1 antibodies to PAP and ricin A chain through a disulfide bond. Both the conjugates were shown earlier to specifically inhibit protein synthesis of Thy 1.1-positive target leukemic cells (AKR SL3). ⋯ These observations indicate that the use of alternate immunotoxins having an immunologically distinct toxin polypeptide may be necessary for tumor therapy during relapse, as exposure to the conjugates results in the formation of specific neutralizing anti-toxin antibodies. The anti-toxin antibodies did not prevent the binding of immunotoxin to target cells. Nevertheless, preincubation of conjugate with anti-toxin antibodies specifically blocked the respective conjugate-induced inhibition of polyuridylic acid translation in a cell-free assay system.
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Serum deoxythymidine-5'-triphosphatase (dTTPase) levels were determined in 71 patients with large bowel cancers at different clinical stages: 10 patients in Duke's Stage A; 37, in Duke's Stage B; and 24, in Duke's Stage C. The dTTPase values of patients in Duke's Stage B and C are significantly elevated over normal healthy controls, and a correlation was observed between tumor stage and dTTPase activity. ⋯ In all patients, carcinoembryonic antigen levels were determined along with dTTPase values, and both sets of data were correlated with each other indicating a correlation coefficient of zero. So, if both dTTPase and carcinoembryonic antigen are taken into account, the sensitivity of detection of colorectal carcinomas rises to 66% for all patients and to 92% for patients with a colorectal carcinoma of Duke's Stage C.
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A newly synthesized platinum analogue, cis-1,1-diaminomethylcyclohexaneplatinum(II) sulfate (TNO-6), was compared with cis-diamminedichloroplatinum(II) (cis-DDP) for antitumor activity and nephrotoxicity. Antitumor activity was determined in an IgM immunocytoma model in the LOU/M rat. Tumor cells were inoculated on the left flank, and therapy was started when a tumor diameter of 10 to 30 mm was reached. ⋯ For TNO-6, even in the highest dose investigated (2.0 mg/kg twice a week for 7 weeks), no nephrotoxicity was observed on histological examination of kidney and blood urea and creatinine values, whereas for cis-DDP nephrotoxicity was still present in the lowest dose investigated (0.5 mg/kg). From the comparison of the antitumor activity and nephrotoxicity of TNO-6 and cis-DDP, administered i.p. in 5% glucose solution, it is concluded that both drugs have comparable antitumor activity and potency. In contrast to the effects of cis-DDP, no nephrotoxicity was observed with TNO-6; thus, TNO-6 might be a good alternative to cis-DDP in avoiding nephrotoxicity during platinum therapy.