Consider von Hippel-Lindau syndrome in young patients presenting with retinal angioma and phaeochromocytoma.
Explore the source record for details and available documents.
Adrenal Gland Neoplasms↗
Biomedical subjects
P Cozzi
Publications and source records attributed to P Cozzi.
Traumatic left shoulder fracture masking aggressive granuloblastic sarcoma in a CML patient.
Explore the source record for details and available documents.
Accidents, Traffic↗
Distamycin derivatives as potential anticancer agents.
Distamycin A was used as DNA minor groove sequence-selective vector of alkylating functions and led to the synthesis of compounds endowed with relevant cytotoxic and antitumor activity. In particular, tallimustine (Pharmacia), a benzoic acid nitrogen mustard derivative of distamycin, showed excellent antitumor activity against murine transplanted solid tumors and human xenografts, and, in the early 1990s, prompted several groups to search for new cytotoxic agents derived from distamycin. Unfortunately, tallimustine showed severe myelotoxicity and its clinical development was discontinued. Nevertheless this compound has represented an important model for the design of new cytotoxic minor groove binders derived from distamycin and distamycin-like frames. Some recently reported derivatives of distamycin-like frames with high cytotoxicity and antitumor activity also show significantly improved cytotoxicity/myelotoxicity ratio, which promises drugs with clinical efficacy. Distamycin-derived cytotoxics have been extensively reviewed in the recent past. This review will focus on cytotoxics derived structurally from distamycin or distamycin-like frames disclosed between 1997 and the third quarter of 2000.
Journal Article↗
Phenyl sulfur mustard derivatives of distamycin A.
The design, synthesis, and cytotoxic activity of novel benzoyl and cinnamoyl sulfur mustard derivatives of distamycin A are described and structure activity relationships are discussed. These sulfur mustards are more potent cytotoxics than corresponding nitrogen mustards in spite of the lower alkylating power, while their sulfoxide analogues are substantially inactive. Cinnamoyl sulfur mustard derivative (7) proved to be one of the most active distamycin-derived cytotoxics, about 1000 times more potent than melphalan.
Distamycins↗
Synthesis and antitumor activity of new benzoheterocyclic derivatives of distamycin A.
The design, synthesis, and in vivo and in vitro antileukemic activity of a novel series of compounds (13-22 and 34), in which different benzoheterocyclic rings, bearing a nitrogen mustard or a benzoyl nitrogen mustard or an alpha-bromoacryloyl group as alkylating moieties, are tethered to a distamycin frame, are reported, and structure-activity relationships are discussed. The new derivatives were prepared by coupling nitrogen mustard-substituted, benzoyl nitrogen mustard-substituted, or alpha-bromoacryloyl-substituted benzoheterocyclic carboxylic acids 23-32 with desformyldistamycin (33) or in one case with its two-pyrrole analogue 35. With very few exceptions, the activities of compounds bearing the same alkylating moiety are slightly affected by the kind of the heteroatom present on the benzoheterocyclic ring. All novel compounds, with one exception, showed in vitro activity against L1210 murine leukemia cell line comparable to or better than that of tallimustine. The compounds in which the nitrogen mustard and the alpha-bromoacryloyl moieties are directly linked to benzoheterocyclic ring showed potent cytotoxic activities (IC(50) ranging from 2 to 14 nM), while benzoyl nitrogen mustard derivatives of benzoheterocycles showed reduced cytotoxic activities, and one compound (16) of this cluster was the sole derivative devoid of significant activity. Compound 18, a 5-nitrogen mustard N-methylindole derivative of distamycin, showed the best antileukemic activity in vivo, with a very long survival time (%T/C = 457), significantly increased in comparison to tallimustine (%T/C = 133), and was selected for further extensive evaluation. Arrested polymerase chain reaction and direct DNA fragmentation assays were performed for compound 18 and the structurally related compounds 13-17 and 19. The results obtained have shown that both alkylating groups and oligopeptide frames play a crucial role in the sequence selectivity of these compounds.
Acrylamides↗
Cytotoxic halogenoacrylic derivatives of distamycin A.
The design, synthesis, in vitro and in vivo activities of a series of halogenoacrylic derivatives of distamycin A are described. The structure-activity relationships indicate a key role of the reactivity of alpha-halogenoacrylic moiety. The reactivity and the putative alkylating mechanism of these compounds are different from those of the nitrogen mustards and possibly based on a Michael type reaction. This supports the hypothesis that these compounds represent a class of minor groove binders mechanistically different from tallimustine.
Animals↗
Cytotoxic alpha-bromoacrylic derivatives of distamycin analogues modified at the amidino moiety.
The design, synthesis, in vitro and in vivo activities of novel alpha-bromoacrylic derivatives of distamycin A, modified at the amidino moiety by the replacement with basic or non-basic groups are reported. In spite of the relevance of these modifications of distamycin frame, the new derivatives are potent cytotoxics. The presence of the amidino moiety, is, therefore; not an absolute requirement for the activity. In particular due to a favorable myelotoxicity/cytotoxicity ratio, guanidino derivative PNU 166196 was selected for clinical development.
Amidines↗
Recent outcome in the field of distamycin-derived minor groove binders.
DNA minor groove binders represent a class of cytotoxic antitumor agents whose DNA sequence specificity may lead to a high selectivity of action. Tallimustine, benzoyl nitrogen mustard derivative of distamycin A, showed excellent antitumor activity in the preclinical tests, but as other minor groove binders, showed severe myelotoxicity. Novel nitrogen mustard derivatives of distamycin showing improved activity profile, have been identified recently. Moreover, a series of alpha-halogenoacrylamido derivatives of distamycin-like frames, in which the typical amidino moiety has been replaced with other moieties, was found to show cytotoxic and antitumor activity and cytotoxicity/myelotoxicity ratio improved significantly in comparison to tallimustine. The structural features of the alkylating moieties and binding frames, of distamycin and distamycin-like derivatives disclosed recently are discussed.
Animals↗
DNA sequence-recognizing properties of minor groove alkylating agents. Effects of the replacement of N-methylpyrrole by an N-methylimidazole on tallimustine and its own homologue.
The linkage of an heterocycle, like N-methylimidazole, to minor DNA groove binders containing two or three pyrroles lead to a new class of oligopeptides with reduced antitumor activity both in vitro and in vivo if compared to tallimustine (CAS 115308-98-0) and its tetrapyrrole homologue 9. In the present paper is reported the correlation between the cytoxicity of tallimustine and its derivatives 9-11 with their ability to inhibit polymerase chain reaction (PCR) amplification of oestrogen receptor and Ha-ras gene sequences, containing A + T rich and G + C rich regions, respectively. Tallimustine and its tetrapyrrole homologue 9 were found to have higher sequence selectivity for the human oestrogen receptor (ER) gene with respect to the relative imidazole-containing analogues.
Animals↗
Novel benzoyl nitrogen mustard derivatives of pyrazole analogues of distamycin A: synthesis and antileukemic activity.
The design and synthesis of novel benzoic acid mustard (BAM) derivatives of distamycin A bearing one or more pyrazole rings replacing the pyrrole rings of the latter are described. In vitro and in vivo activities against L1210 leukemia are reported and discussed. Some of these compounds show an activity profile comparable to tallimustine 1. All the compounds bearing the pyrazole ring close to the BAM moiety show reduced cytotoxicity in comparison to derivatives characterized by the BAM linked to a pyrrole: the same effect has not been observed when occurring at the amidine terminus of the oligopeptidic frame.
Animals↗
Alpha-bromoacryloyl derivative of distamycin A (PNU 151807): a new non-covalent minor groove DNA binder with antineoplastic activity.
PNU 151807 is a new synthetic alpha-bromoacryloyl derivative of distamycin A. In the present study we investigated the DNA interaction and the mechanism of action of this compound in parallel with the distamycin alkylating derivative, tallimustine. PNU 151807 possesses a good cytotoxic activity in in vitro growing cancer cells, even superior to that found for tallimustine. By footprinting experiments we found that PNU 151807 and tallimustine interact non-covalently with the same AT-rich DNA regions. However, differently from tallimustine, PNU 151807 failed to produce any DNA alkylation as assessed by Taq stop assay and N3 or N7-adenine alkylation assay in different DNA sequences. PNU 151807, like tallimustine, is able to induce an activation of p53, and consequently of p21 and BAX in a human ovarian cancer cell line (A2780) expressing wild-type p53. However, disruption of p53 function by HPV16-E6 does not significantly modify the cytotoxic activity of the compound. Flow cytometric analysis of cells treated with equitoxic concentrations of PNU 151807 and tallimustine showed a similar induction of accumulation of cells in the G2 phase of the cell cycle but with a different time course. When tested against recombinant proteins, only the compound PNU 151807 (and not tallimustine or distamycin A) is able to abolish the in vitro kinase activity of CDK2-cyclin A, CDK2-cyclin E and cdc2-cyclin B complexes. The results obtained showed that PNU 151807 seems to have a mechanism of action completely different from that of its parent compound tallimustine, possibly involving the inhibition of cyclin-dependent kinases activity, and clearly indicate PNU 151807 as a new non-covalent minor groove binder with cytotoxic activity against cancer cells.
Animals↗
PNU 157977: a new potent antitumour agent exhibiting low in vivo toxicity in mice injected with L1210 leukaemia cells.
The design, synthesis, in vitro and in vivo activity against L1210 murine leukaemia of the dibromo nitrogen mustard derivative of 2, called PNU 157977, is described and the structure-activity relationship discussed. This dibromo derivative is almost two orders of magnitude more cytotoxic than the dichloro counterpart having the same oligopeptidic chain (IC50 2.7 ng/ml versus 225 ng/ml), and it showed in vivo an increased survival time which is 5- and 3-fold longer than that of tallimustine and 2 (and T/C 750 versus 133 and 213) respectively. Moreover PNU 157977 shows activity against the M5076 solid tumour markedly inferior to that of the closely analogous 2. Footprinting experiments conducted using the oestrogen receptor PCR probe as the footprinting target molecule show that PNU 157977 possesses a different sequence-specific alkylation and greater cleavage activity than either 2 or tallimustine.
Animals↗
Differential effects of cyclosporine A after acute antigen challenge in sensitized cats in vivo and ex vivo.
1. We determined the effect of cyclosporine A (CsA) treatment on mast cell degranulation and lung resistance (R(L)) in vivo, and tracheal smooth muscle (TSM) contraction ex vivo after antigen challenge in sensitized cats. We also determined the direct effects of addition of CsA to the tissue bath on antigen-induced responses of TSM in vitro. 2. Cats (n=10) were sensitized by i.m. injection of Ascaris suum antigen (AA); 5 cats (CsA+) received CsA twice daily for 2 weeks before acute antigen challenge in doses sufficient to suppress interleukin-2 secretion from feline peripheral blood mononuclear cells ex vivo. 3. Lung resistance increased comparably within 10 min of exposure to AA (P<0.03). Histamine content in bronchoalveolar lavage fluid from both groups increased comparably within 30 min of antigen challenge, from undetectable levels to 542+/-74 pg ml(-1) post AA for CsA+ and from 74+/-19 pg ml(-1) at baseline, to 970+/-180 pg ml(-1) post AA CsA- (P<0.05; P=NS vs CsA+). 4. In excised TSM, active tension elicited by exposure to AA in vitro was 107+/-38% KCl in the CsA+ group vs 144+/-56% KCl in the CsA- group (P=NS). However, contraction of TSM (n=4) harvested from both groups was abolished or greatly diminished after AA challenge when tissues were pre-incubated with 1 microM CsA in vitro (8+/-8% KCl, P<0.05 vs CsA+ and CsA-). This was associated with inhibited release of 5-hydroxytryptamine into the organ bath fluid of tissues treated with CsA in vitro only. 5. We demonstrated that CsA treatment in vivo does not inhibit the early phase asthmatic response or mast cell degranulation following antigen challenge in sensitized cats. Additionally, the effects of CsA on mast cell function ex vivo do not reflect lack of effects of CsA on mast cell function in vivo in this animal model of atopic asthma.
Animals↗
Cytotoxics derived from distamycin A and congeners.
Distamycin A is an antibiotic, characterised by an oligopeptidic pyrrolocarbamoyl frame ending with an amidino moiety, which binds reversibly to DNA minor groove with high selectivity for TA-rich sequences and shows antiviral and antiprotozoal activity. Distamycin was used as DNA sequence selective vector of alkylating functions, leading to a substantial increase of cytotoxicity in comparison to that, very weak, of distamycin itself. The benzoyl nitrogen mustard derivative of desformyldistamycin, tallimustine, was selected as a candidate antineoplastic drug in view of its strong activity against a series of experimental tumors. Tallimustine, like distamycin, shows DNA selective binding to TA-rich sequences but its cytotoxicity is not associated with DNA strand breaks and interstrand crosslinking, at variance with classical phenyl nitrogen mustards. Tallimustine represents an important model for the design of new minor groove alkylating agents derived from distamycin and analogues, including the so-called lexitropsins, sequence-reading oligopeptides in which one or more N-methyl-pyrrole units of distamycin are replaced by imidazole or other rings. The structural features of the alkylating moieties and binding frames, the antitumor activities and the mechanism of action of most representative cytotoxics derived from distamycin and congeners are discussed. Some of these, recently reported, show an activity profile apparently superior to tallimustine. Finally, a concise survey of representative hybrid compounds in which known non-alkylating cytotoxic agents or their active moieties have been tethered to distamycin and congeners is presented and briefly discussed. These compounds witness the attention paid to this approach on the basis of the interest for the DNA binding features of distamycin A.
Alkylating Agents↗
Effect of stimulus intensity on spine recorded somatosensory evoked potential in dogs.
OBJECTIVE: To investigate the effect of stimulus intensity on the characteristics of the spine recorded somatosensory evoked potentials (SEP) in dogs. ANIMALS: 11 healthy Beagles, 1 to 2 years old. DESIGN AND PROCEDURE: In 10 dogs, square-wave stimuli (0.1-ms duration, 4 Hz) were delivered through needle electrodes inserted close to the right tibial nerve at the tibiotarsal joint. A standard stimulus strength (reference effective stimulus [RS]) was established for each dog by determining the stimulus necessary to induce a maximal M wave (muscle evoked potential) in the plantar interosseus muscles. The polarity of the stimulating electrodes was then reversed, and an SEP was recorded at the level of the T13-L1 interarcuate ligament. Subsequently, stimuli at fractions (1/4x, 1/2x) and multiples (2x, 4x) of RS were delivered. Recordings, using 10x RS stimuli, also were obtained in 2 dogs; in 1 of them, the recordings were obtained before and after curarization. In each instance, the latencies and the amplitudes of the first 3 reproducible deflections were measured and evaluated. RESULTS: The SEP waveform recorded at the T13-L1 level using RS was similar in all dogs; at least 3 deflections were recognized. Altering stimulus intensity did not significantly change latency of the first 3 peaks; conversely, amplitudes of the first 3 peaks increased (P < 0.01) when the stimulus intensity was increased from 1/4x RS to 1x RS. Stimulation at 10x RS induced the recording of a large potential, which was suppressed by the curarization. CONCLUSION: Only slight variations affect latency data through a wide range of stimulus intensities; latency measurement can be considered a robust tool in the vicinity of RS. Slight variations in the electrode position during an SEP session should not invalidate the results. Differences in the definition of the stimulus intensity among laboratories should not preclude the comparison of the results.
Analysis of Variance↗
Sequence-specific DNA alkylation of novel tallimustine derivatives.
Three different groups of analogs of the sequence-specific minor groove alkylator tallimustine (2) have been synthesized and investigated. Within group I, the dibromo nitrogen mustard (3) and the half-mustard (4) are more cytotoxic (IC50 = 0.6 and 40 ng/ml respectively) than tallimustine (IC50 = 50.3 ng/ml) against L1210 cells with high reactivity against the region 5'-TTTTGA. The diol derivative (6) and the difluoro nitrogen mustard (5) were not cytotoxic against L1210 cells and did not show any detectable DNA alkylation. The two compounds modified in the propionamidine terminus (7 and 8, group II), showed lower cytotoxic potency (IC50 = 130 and 94 ng/ml respectively) against L1210 cells than tallimustine (IC50 = 50.3 ng/ml) and a loss of in vitro sequence specificity for DNA alkylation. Considering the compounds in which the pyrrole rings were replaced by one (9) or two (10) pyrazole rings, compound 9 was not significantly cytotoxic against L1210 cell line and was apparently unable to produce alkylation on the DNA fragments tested, while compound 10 showed decreased cytotoxicity (IC50 = 114 ng/ml) and no modification in the pattern and intensity of DNA alkylation. The data obtained in this work suggest that it is possible to increase tallimustine potency by modifying the nitrogen mustard moiety. Moreover, the sequence specificity of DNA alkylation appears to be affected by the modification of the propionamidino moiety but not by the isosteric modification of the pyrrole rings. The correlation between cytotoxicity and alkylation pattern suggests that tallimustine exerts its cytotoxicity through DNA sequence-specific alkylation of the adenine located in the sequence 5'-TTTTGA.
Animals↗
Synthesis, chemical solvolytic stability and preliminary biological evaluation of (+/-)-N-Boc-CPzI: a pyrazole analog of the left-hand segment of the antitumor agent CC-1065.
Explore the source record for details and available documents.
Animals↗