RÉSUMÉ
In experimental animals with tumors it was studied antitumor activity of spirocyclic hydroxamic acids which could be classified as targeted agents as their target was enzyme histonedeacetylase, which was involved in the neoplastic process. The results showed that the hydroxamic acids were chemosensitizers for anticancer agents increasing their efficacy and enabling the researchers to reduce significantly the therapeutic dose. Also it was showed that hydroxamic acid, containing nitrogen mustard, was effective in the action on tumors with phenotype and genotype of multidrug resistance.
Sujet(s)
Antinéoplasiques/pharmacologie , Multirésistance aux médicaments/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Acides hydroxamiques/pharmacologie , Tumeurs expérimentales/traitement médicamenteux , Animaux , Antinéoplasiques/usage thérapeutique , Cyclophosphamide/administration et posologie , Inhibiteurs de désacétylase d'histone , Acides hydroxamiques/usage thérapeutique , Leucémie P388/traitement médicamenteux , Méthotrexate/administration et posologieRÉSUMÉ
Treatment with low doses (1/10 of LD50) of cisplatin and platinum (IV)-nitroxyl complex VS118 [e-ammin-d-(4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl)-a,f-bi s(acetate)-b,c-dichlorplatinum (IV)] was followed by a synergistic therapeutic effect (a 100% cure of animals) as compared with monotherapy with either drug. There was no synergistic increase in toxicity. The rates of resistance development decreased in the following order: P388/cPt+VS118, P388/cPt, P388/VS118. Resistant strains P388/cPt+VS18 and P388/VS118 were highly sensitive to doxorubicin, etoposide and cyclophoshamide. Further research in cPt+VS 118 combinations should be continued.
Sujet(s)
Antinéoplasiques/pharmacologie , Cisplatine/pharmacologie , Résistance aux médicaments antinéoplasiques , Leucémie P388/traitement médicamenteux , Composés organiques du platine/pharmacologie , Composés du platine/pharmacologie , Animaux , Antinéoplasiques/administration et posologie , Antinéoplasiques/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Cisplatine/administration et posologie , Cisplatine/effets indésirables , Cyclophosphamide/pharmacologie , Doxorubicine/pharmacologie , Synergie des médicaments , Étoposide/pharmacologie , Souris , Oxydes d'azote/administration et posologie , Oxydes d'azote/effets indésirables , Oxydes d'azote/pharmacologie , Composés organiques du platine/administration et posologie , Composés du platine/administration et posologie , Composés du platine/effets indésirablesRÉSUMÉ
The investigation has established a potential of low-dosage chemotherapy with cytostatics when used in combination with nitric oxide (NO) donor. Such regimen resulted in more animals being cured of leukemias P388 and L1210 and longer survival. Similar effect was reported with transplantable intracerebral leukemia P388 in which case mean survival after cyclophosphamide plus NO-donor was three times as high as that after cyclophosphamide alone. Combination therapy also promoted animetastatic effect: melanoma B16 inhibition by cyclophosphamide alone was 50% vs. 80% after cyclophosphamide plus NO-donor. NO-donor inhibited development of drug resistance to cyclophosphamide.
Sujet(s)
Antinéoplasiques alcoylants/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Cyclophosphamide/pharmacologie , Leucémie P388/traitement médicamenteux , Mélanome expérimental/traitement médicamenteux , Donneur d'oxyde nitrique/pharmacologie , Tumeurs de l'abdomen/traitement médicamenteux , Animaux , Tumeurs du cerveau/traitement médicamenteux , Cisplatine/administration et posologie , Doxorubicine/administration et posologie , Résistance aux médicaments antinéoplasiques , Humains , Transplantation tumoraleRÉSUMÉ
It was demonstrated that radiosensitizer AK-2123 of the triazole group significantly enhanced the sensitivity of MDR-strains of P388 murine leukemia (reported by the authors earlier) to mitomycin C (MMC). There was a direct correlation between the modulating effect of AK-2123 and dose increase from 1 to 10 mg/kg. The effect depended on the initial sensitivity of the MMC-resistant strain which in turn correlated with the absence or presence of sorcin (cytosole low-molecular Ca(2+)-binding protein) gene coamplification in the mdr-amplicon. Since AK-2123 was reported earlier by us to disrupt active Ca(2+)-transport, it is suggested that the modulating effect of the radiosensitizer was at least partially due to said disruption. AK-2123 exerted no antitumor action of its own whatsoever. It could neither modify the sensitivity of parent strain P388 to MMC, nor overcome the cross resistance of one of the MDR-tumor strains under study to such drugs as etoposide and adriablastin.