Cancer research
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Cancer chemotherapy may be improved by increasing antineoplastic drug specificity for tumor cells. We have synthesized a glucuronide prodrug that can be enzymatically converted to an antineoplastic agent at tumor cells that are able to bind beta-glucuronidase-monoclonal antibody conjugates. The glucuronide prodrug BHAMG, the tetra-n-butyl ammonium salt of (p-di-2-chloroethylaminophenyl-beta-D-glucopyranoside) uronic acid, was 150 times less toxic than the parent drug, N,N-di-(2-chloroethyl)-4-hydroxyaniline, to HepG2 human hepatoma cells and over 1000-fold less toxic than the parent drug to AS-30D rat hepatoma cells in vitro. ⋯ The concentration of BHAMG causing 50% inhibition of AS-30D cellular protein synthesis was reduced over 1000-fold, from greater than 770 microM to less than 0.74 microM after these cells were preincubated with RH1-beta G. Specificity of BHAMG activation at antigen-positive cells was shown by monoclonal antibody RH1 blocking of RH1-beta G conversion of BHAMG to toxic drug and by the inability of BHAMG to be converted to active drug when antigen-negative control cells were preincubated with RH1-beta G. Our results show that the targeted-beta-glucuronidase activation of BHAMG can increase the specificity of chemotherapy for rat hepatoma in vitro and suggest that the targeted activation of glucuronide prodrugs may be useful for cancer therapy.
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Prostate growth curves were estimated from serial prostate-specific antigen (PSA) measurements on frozen sera in three groups of men: (a) 16 men with no prostatic disease by urological history and examination; (b) 20 men with a histological diagnosis of benign prostatic hyperplasia (BPH) who had undergone simple prostatectomy; and (c) 18 men with a histological diagnosis of prostate cancer. The median number of repeated PSA measurements over an 8- to 26-yr period prior to histological diagnosis or exclusion of prostate disease was eight and 11 for noncancer and cancer subjects, respectively. Predicted rates of change in PSA (PSA velocity) were linear and curvilinear for control and BPH subjects, respectively. ⋯ Subjects with local/regional and advanced/metastatic cancer had similar PSA doubling times of 2.4 +/- 0.6 yr and 1.8 +/- 0.2 yr, respectively. These data are consistent with what is known about prostatic growth with age in men without prostate disease and BPH, and the kinetics of prostate cancer growth. Estimates of prostatic growth rate from changes in PSA may be useful clinically in management of men with prostate disease.
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Rat R2k rhabdomyosarcoma cells were transfected with the human H-ras oncogene, which resulted in increased resistance to cell kill in vitro by a single dose of 137Cs gamma-rays. A subline carrying one oncogene showed an increase in the quasi-threshold dose (Dq) from 0.88 to 1.48 Gy. Another subline containing six oncogenes not only had an increased Dq of 1.59 Gy but also showed an increase in the dose reducing cell survival to a fraction of e-1 = 0.37 (D0) from 1.25 to 1.76 Gy. ⋯ This means that a 3.0 times higher cumulated absorbed dose would be needed for enhancing the cure rate from 32% to 75% in the subline with H-ras than for the parental line. With 2 Gy/fraction the difference in extra doses required for obtaining isolevels of cure rates was found to be small, a factor of 1.4. The results indicate that in the course of fractionated irradiation with 1 Gy/fraction, in vivo repair is much more efficient in the transfected subline.
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The spermine analogues, N1,N12-bis(ethyl)spermine (BESPM), N1,N11-bis(ethyl)norspermine (BENSPM), and N1,N14-bis(ethyl)-homospermine (BEHSPM) behave similarly in down-regulating the key polyamine biosynthetic enzymes, ornithine and S-adenosylmethionine decarboxylase, but differ distinctly in their abilities to induce the polyamine catabolic enzyme, spermidine/spermine-N1-acetyltransferase; BENSPM is 6-fold more effective than BESPM in increasing spermidine/spermine-N1-acetyltransferase activity and BEHSPM is 10-fold less effective. Since MALME-3 human melanoma cells are extremely responsive to spermidine/spermine-N1-acetyltransferase induction (i.e., increases greater than 200-fold) and since this induction correlates with growth inhibition among melanoma cell lines, the ability of these homologues to inhibit the growth of MALME-3 xenografts was examined. Analogues were administered i.p. three times per day (i.e., every 8 h) for 6 days at the following doses per injection: BEHSPM, 1.5, 3, or 6 mg/kg; BESPM, 10, 20, or 40 mg/kg; BENSPM, 20, 40, or 80 mg/kg. ⋯ The rank order of analogue host toxicity as indicated by weight loss was opposite that for antitumor activity, BEHSPM was most toxic, BESPM, intermediate, and BENSPM, least toxic. Thus, the most effective of the three homologues, BENSPM, was best tolerated, and produced an initial tumor regression, full suppression of tumor regrowth during treatment, and sustained inhibition of tumor regrowth for 37 days after treatment stopped. Owing to its potent antitumor activity, mild host toxicity, and novel apparent mechanism of action, BENSPM is being considered for further development toward clinical trial.
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Bombesin-like peptides (BLP) produced by pulmonary neuroendocrine cells have many physiological actions which are relevant to the pathobiology of cigarette smoking. The objectives of this study were to determine whether cigarette smokers excrete increased levels of BLP in their urine compared with nonsmokers, to determine the relationship between BLP levels in urine and bronchoalveolar lavage (BAL) fluid, and whether urinary BLP levels are merely a reflection of exposure to cigarette smoke. Simultaneous BAL fluid and urine samples were obtained from ten clinically normal smokers and 22 normal nonsmoker volunteers. ⋯ Finally, all smokers with detectable BLP levels in BAL fluid had detectable urinary BLP levels, and there was a positive correlation between BLP levels in urine and BAL fluid (r = 0.625, P less than 0.001). We conclude that a subgroup of asymptomatic cigarette smokers exhibited increased BLP levels, measurable in both urine and BAL fluid, which precede the onset of clinically detectable disease and which are not strictly dependent on smoking intensity. We speculate that smokers with increased BLP levels may have a greater risk for smoking-related diseases.