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The multiple antigenic peptide (MAP) system for presenting epitopes to the immune system has been studied with an immunogenic foot-and-mouth disease virus (FMDV) peptide comprising amino acids 141-160 of protein VPI. Neutralizing antibody responses known to protect guinea-pigs against challenge infection were obtained with a single inoculation of 08-4 μg of peptide, presented as an octamer or a tetramer, whereas 20 μg of a dimer were required to evoke a similar level of antibody. A monomeric preparation did not elicit measurable levels of neutralizing antibody at doses up to 20 μg. The octameric MAP was also immunogenic using an aluminium hydroxide adjuvant. Antibodies elicited by the octameric, tetrameric and dimeric constructs differed qualitatively in their reaction with sequences within the 141-160 peptide. Those against the octamer reacted poorly with peptides within the 141-160 sequence, whereas those elicited by the tetramer and dimer reacted preferentially with the peptides covering the N-terminal region. The levels of neutralizing antibody obtained with the octamer and tetramer compare favourably with those obtained when the FMDV peptide is attached to carrier proteins but are lower than, those obtained when it is presented as part of a peptide-hepatitis B virus core particle. Nevertheless, the ability to elicit protective levels of neutralizing antibody without the use of a carrier protein would be a distinct advantage in the development of synthetic peptide vaccines. [ABSTRACT FROM AUTHOR]

Objectives: We hypothesize that prostate cancer (PC) patients who achieve and maintain an undetectable prostate-specific antigen (UD-PSA) on androgen deprivation therapy (ADT) have a predominantly androgen-dependent cancer cell population sensitive to apoptosis that allows for a prolonged time off ADT. This study summarizes patient- and treatment-related factors associated with a prolonged time off ADT in patients electing intermittent androgen deprivation (IAD)., Methods: Hormone-naïve patients with PC were treated with ADT using an antiandrogen and a luteinizing-hormone-releasing hormone-agonist. Of 255 consecutive patients, 216 (85%) achieved a UD-PSA (< 0.05 ng/ml). Ninety-three (43%) of 216 elected to stop ADT after maintaining a UD-PSA for a median of one year. Patients were followed off therapy and advised to restart ADT if the PSA level reached > or = 5.0 ng/ml. Forty-one patients received finasteride as part of IAD induction and as maintenance off therapy; these patients are excluded from the current study and are the focus of another publication. The remaining 52 patients are assessable for response being either in the off-phase of IAD > or = 1 year or having restarted IAD., Results: In the first IAD cycle, the median duration of the on-phase of IAD was 16 months (mean 19.0 months, range 3.6-71 months), and the median off-phase duration was 15.5 months (mean 24.1 months, range 3.2-87+ months). In 28 patients who maintained a UD-PSA for > or = 1 year, their median off-phase duration was 29 months (mean 35.8 months, range 7.8-87+ months), with nine (32%) still off IAD after a median follow-up of 62 months. Significant (p < 0.05) independent factors associated with prolonged off-phase duration by multivariate analysis included UD-PSA on ADT > or = 1 year (p = 0.010), PSA-only recurrence after local therapy (p = 0.039), and reaching a testosterone level > or = 150 ng/dl in > or = 4 months off ADT (p = 0.041). After a median of 66 months of follow-up, only one (2%) patient developed androgen-independent PC., Conclusions: Hormone-naïve patients who achieve and maintain a UD-PSA for at least one year during ADT may initiate IAD and anticipate a prolonged off-phase duration. Attainment of a UD-PSA on ADT may serve as an in vivo sensitivity test of a patient's tumor cell population, and allow for better selection of those best suited for IAD.

Gastrin-releasing peptide (GRP) is a neuroendocrine hormone that may be involved in the pathophysiology of small cell lung carcinoma. We describe carboxylterminal peptide analogues of GRP and bombesin, a 14-residue amphibian homologue, that were modeled after the antagonist [Leu13-psi(CH2NH)-Leu14]bombesin and retained the psi bond. Three novel peptides contained a Leu insertion amino to the psi bond, i.e. ... Leu13Leu14 psi X (residues numbered after bombesin) where X = LeuNH2 or norleucine-NH2). The Leu-insertion analogues behaved as pure partial agonists/antagonists when examined for the ability to stimulate [3H]thymidine incorporation into quiescent Swiss 3T3 cells (agonist activity) and to diminish the agonist response of GRP (antagonist activity). A time course of [3H]thymidine incorporation into quiescent cells indicated maximal incorporation at 20-h post-peptide addition for bombesin and GRP and a Leu-insertion peptide, but the extent of the incorporation for the Leu-insertion peptide was half that of GRP and bombesin. The agonist dose responses of the Leu-insertion peptides (EC50 values of 1-10 nM) paralleled GRP and bombesin, but the maximal response of the Leu-insertion peptides, even at concentrations as high as 10(-4) M, was half the maximal value of GRP or bombesin. High concentrations of the Leu-insertion peptides antagonized 10 nM GRP (a concentration that produced a near-maximal GRP response) yielding a response that was half the maximal value of GRP and equivalent to the maximal response of the Leu-insertion peptides alone. Analogues of the form ... Leu13 psi X behaved as complete antagonists. The KD values of the Leu-insertion peptides for competitive binding versus 125I-GRP (2-50 nM) were as potent as parent ... Leu14 agonists. Stability studies indicated that peptide potencies for both agonist and antagonist activities diminished upon peptide incubation in medium or on cells. The results suggested that, for the Leu-insertion peptides, degradation into distinct products with different activities was not responsible for their partial agonist/antagonist behavior. Computer-generated molecular modeling studies indicated that the novel structures could adopt energy minimized conformations for either an agonist or an antagonist as proposed earlier (Coy, D.H., Heinz-Erian, P., Jiang, N.-Y., Sasaki, Y., Taylor, J., Moreau, J.-P., Wolfrey, W.T., Gardner, J.D., and Jensen, R. T. (1988) J. Biol. Chem. 263, 5056-5060).