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1.
Pediatr Hematol Oncol ; 22(1): 49-52, 2005.
Article in English | MEDLINE | ID: mdl-15770831

ABSTRACT

Accidental extravasation of vesicant chemotherapy may cause important tissue injuries. Nowadays, the majority of authors propose topical dimethyl sulfoxide (DMSO), with or without local cooling, as the treatment of choise efor anthracyclines extravasation. No significant toxicity has been reported when DMSO is used as topical treatment. This report describes a case of local toxicity consisting of severe pain after its use in a pediatric patient. An illustration shows the extravasation area.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dimethyl Sulfoxide/adverse effects , Extravasation of Diagnostic and Therapeutic Materials/drug therapy , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Child, Preschool , Dimethyl Sulfoxide/therapeutic use , Female , Humans , Leukemia, Myelomonocytic, Acute/drug therapy
2.
J Biol Chem ; 276(39): 36652-63, 2001 Sep 28.
Article in English | MEDLINE | ID: mdl-11463790

ABSTRACT

Few gastrointestinal hormones/neurotransmitters have high affinity peptide receptor antagonists, and little is known about the molecular basis of their selectivity or affinity. The receptor mediating the action of the mammalian bombesin (Bn) peptide, gastrin-releasing peptide receptor (GRPR), is an exception, because numerous classes of peptide antagonists are described. To investigate the molecular basis for their high affinity for the GRPR, two classes of peptide antagonists, a statine analogue, JMV594 ([d-Phe(6),Stat(13)]Bn(6-14)), and a pseudopeptide analogue, JMV641 (d-Phe-Gln-Trp-Ala-Val-Gly-His-Leupsi(CHOH-CH(2))-(CH(2))(2)-CH(3)), were studied. Each had high affinity for the GRPR and >3,000-fold selectivity for GRPR over the closely related neuromedin B receptor (NMBR). To investigate the basis for this, we used a chimeric receptor approach to make both GRPR loss of affinity and NMBR gain of affinity chimeras and a site-directed mutagenesis approach. Chimeric or mutated receptors were transiently expressed in Balb/c 3T3. Only substitution of the fourth extracellular (EC) domain of the GRPR by the comparable NMBR domain markedly decreased the affinity for both antagonists. Substituting the fourth EC domain of NMBR into the GRPR resulted in a 300-fold gain in affinity for JMV594 and an 11-fold gain for JMV641. Each of the 11 amino acid differences between the GRPR and NMBR in this domain were exchanged. The substitutions of Thr(297) in GRPR by Pro from the comparable position in NMBR, Phe(302) by Met, and Ser(305) by Thr decreased the affinity of each antagonist. Simultaneous replacement of Thr(297), Phe(302), and Ser(305) in GRPR by the three comparable NMBR amino acids caused a 500-fold decrease in affinity for both antagonists. Replacing the comparable three amino acids in NMBR by those from GRPR caused a gain in affinity for each antagonist. Receptor modeling showed that each of these three amino acids faced inward and was within 5 A of the putative binding pocket. These results demonstrate that differences in the fourth EC domain of the mammalian Bn receptors are responsible for the selectivity of these two peptide antagonists. They demonstrate that Thr(297), Phe(302), and Ser(305) of the fourth EC domain of GRPR are the critical residues for determining GRPR selectivity and suggest that both receptor-ligand cation-pi interactions and hydrogen bonding are important for their high affinity interaction.


Subject(s)
Peptides/chemistry , Receptors, Bombesin/antagonists & inhibitors , Receptors, Bombesin/chemistry , 3T3 Cells , Amino Acid Sequence , Amino Acids/chemistry , Animals , Binding Sites , DNA, Complementary/metabolism , Inhibitory Concentration 50 , Kinetics , Methionine/chemistry , Mice , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Phenylalanine/chemistry , Protein Binding , Protein Structure, Tertiary , Rats , Sequence Homology, Amino Acid , Serine/chemistry , Transfection
3.
J Pept Res ; 53(3): 275-83, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10231715

ABSTRACT

Bombesin receptor antagonists are potential therapeutic agents due to their ability to act as inhibitors of cellular proliferation. On the basis of our hypothesis concerning the mechanism of action of gastrin associating an activating enzyme to the receptor and on the results reported in the literature, we have synthesized bombesin analogs which have been modified in the C-terminal part. Potent bombesin receptor antagonists were obtained by replacement of Leu-13 with a statyl residue or with a residue bearing an hydroxyl group in place of the carbonyl function of Leu-13. Several inhibitors were able to recognize the bombesin receptor on rat pancreatic acini and antagonized bombesin stimulated amylase secretion in the nanomolar range. These compounds were also able to recognize the bombesin receptor and to inhibit [3H] thymidine incorporation in 3T3 cells with the same potency.


Subject(s)
Organophosphorus Compounds/chemical synthesis , Receptors, Bombesin/antagonists & inhibitors , 3T3 Cells , Amylases/metabolism , Animals , Dose-Response Relationship, Drug , Inhibitory Concentration 50 , Kinetics , Mice , Models, Chemical , Pancreas/drug effects , Rats , Thymidine/metabolism
4.
J Pept Res ; 51(1): 55-64, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9495592

ABSTRACT

JMV635, a nonapeptide analog of the active terminal nonapeptide segment of bombesin, was tested for its ability to stimulate in vitro amylase release from rat pancreatic acinar cells and to inhibit the binding of gastrin-releasing peptide to rat pancreatic acini. It was found to be a full agonist of bombesin and to recognize the bombesin receptor with moderate potency. The NMR proton assignments of JMV635 were achieved, and the conformations of JMV635 in aqueous solution and in trifluoroethanol at 297 K were determined using two-dimensional COSY, HOHAHA, NOESY and ROESY experiments. In trifluoroethanol, JMV635, like the active part of bombesin, showed a partial alpha-helical structure. These results were confirmed by circular dichroism and refined by restrained molecular dynamic methods. Structure calculations, using the distance and angle restraints obtained from NMR data on JMV635, gave a total of 75 structures which could be aligned to a root mean square deviation of the bond length of 0.007 A and of the valence angle of 1.55 degrees for the backbone atoms of the amino acid residues. The conformation is a well-defined right-handed alpha-helix in the C-terminal Q2-G6 segment and is less structured in the three C-terminal residues.


Subject(s)
Bombesin/analogs & derivatives , Oligopeptides/pharmacology , Amylases/metabolism , Animals , Bombesin/agonists , Circular Dichroism , Magnetic Resonance Spectroscopy , Male , Oligopeptides/chemistry , Pancreas/drug effects , Pancreas/enzymology , Pancreas/metabolism , Rats , Rats, Wistar
5.
Peptides ; 19(1): 57-63, 1998.
Article in English | MEDLINE | ID: mdl-9437737

ABSTRACT

Analogs of bombesin in which the peptide bond between the two last amino acid residues were replaced by a pseudopeptide bond mimicking the transition state analog were evaluated. These compounds were able to recognize the bombesin receptor on isolated rat pancreatic acini with high potency (Ki from 0.60 +/- 0.27 nM to 4.3 +/- 2.3 nM). Although they were devoid of agonist activity, they were able to antagonize bombesin-induced amylase secretion in this model, with potencies in accordance with their affinities (IC50 from 1.6 +/- 0.3 nM to 10.0 +/- 1.7 nM). When tested in vivo in the anesthetized rat, these bombesin receptor antagonists exhibited high potency in inhibiting bombesin-induced pancreatic secretion (H-DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH[CH2-CH(CH3)2]-CHOH-(CH 2)3-CH3, JMV845, was among the most potent compounds with ED50 of 7.82 +/- 2.89 nM in inhibiting bombesin-induced protein secretion). The results of this study showed that replacing the peptide bond between the two last amino acid residues in bombesin by mimicking the transition state analog resulted in in vitro and in vivo potent bombesin receptor antagonists.


Subject(s)
Bombesin/analogs & derivatives , Pancreas/drug effects , Amylases/metabolism , Animals , Binding, Competitive , Bombesin/pharmacology , Dose-Response Relationship, Drug , Gastrin-Releasing Peptide/analogs & derivatives , Gastrin-Releasing Peptide/metabolism , In Vitro Techniques , Male , Pancreas/enzymology , Pancreas/metabolism , Rats , Rats, Wistar , Receptors, Bombesin/antagonists & inhibitors
6.
Regul Pept ; 65(1): 91-7, 1996 Aug 27.
Article in English | MEDLINE | ID: mdl-8876041

ABSTRACT

The peptides of the bombesin family are involved in stimulation of mitogenesis in various cell lines, including cancerous cell lines. Bombesin receptor antagonists are of great interest to inhibit this proliferation. We have synthesized a potent bombesin receptor antagonist, e.g., compound JMV641 [H-DPhe-Gln-Trp-Ala-Val-Gly-His-NH-*CH[CH2-CH(CH3)2]-**CHOH- (CH2)3-CH3 [*(S); **92% of (S) isomer], in which a pseudopeptide bond mimicking the transition state analogue replaced the peptide bond between the two C-terminal residues. This compound was highly potent to dose-dependently inhibit binding of 125I-GRP to Swiss 3T3 cells (IC50 = 0.85 +/- 0.15 nM) and bombesin-stimulated Swiss 3T3 proliferation (pA2 = 8.78). However, compound JMV641 can inhibit bombesin-induced AP-1 regulated genes that are nuclear messengers mediating the actions of signal transduction pathways stimulated by growth factors.


Subject(s)
Oligopeptides/pharmacology , Receptors, Bombesin/antagonists & inhibitors , 3T3 Cells , Amylases/metabolism , Animals , Bombesin/pharmacology , Cell Division/drug effects , Gene Expression Regulation/drug effects , Mice , Signal Transduction , Thymidine/metabolism , Transcription Factor AP-1/metabolism
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