RESUMO
Camptothecin (CPT) is a potent, antitumour drug acting mainly through inhibition of topoisomerase I during the S-phase of the cell cycle. Despite its impressive antitumour activity, clinical development was halted for unpredictable toxic events. Two soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesised to contain CPT (5 wt.% and 10 wt.%). CPT was covalently linked at its alpha-hydroxyl group to the polymers through a Gly-Phe-Leu-Gly- spacer. In-vitro, CPT-conjugates were fairly resistant to hydrolysis in plasma as in buffer at neutral pH (0.2-0. 4% free CPT/h), while elastase and cysteine-proteases were able to release the active drug. Plasma levels in mice after intravenous administration of CPT-conjugates confirmed the modest hydrolysis in plasma. Plasma levels were approximately 5-fold lower than those observed at the highest tolerated dose of CPT administered in classical vehicles. Biodistribution in HT29 human colon carcinoma bearing mice was carried out after i.v. injection of [3H]CPT-conjugate and free [3H]CPT. Radioactivity uptake in tumour was evident only after [3H]CPT-conjugate treatment. Repeated intravenous administration of CPT-conjugates to HT29-bearing mice gave more than 90% tumour inhibition, some complete tumour regressions and no toxic deaths. The improved pharmacological profile on HT29 human colon carcinoma xenografts of the first poly(HPMA)-CPT conjugates might be ascribed to their prolonged intra-tumour retention and sustained release of the active drug.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Autorradiografia , Soluções Tampão , Camptotecina/administração & dosagem , Preparações de Ação Retardada , Células HT29 , Humanos , Hidrólise , Injeções Intravenosas , Cinética , Metacrilatos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Polímeros , Distribuição Tecidual , Transplante HeterólogoRESUMO
FCE 27266, 2,2,'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole carbonyl-imino¿N-methyl-4,2-pyrrole¿carbonylimino])-bis- (1,5-naphthalene) disulfonic acid, is a noncytotoxic compound able to complex bFGF, PDGF beta, IL-8, VEGF and IL-1 beta and to inhibit the binding to their receptors. A single intravenous treatment 48 h prior to intravenous injection with tumor cells was associated with 60% inhibition of lung metastasis from B16F10 murine melanoma and 82% inhibition of liver metastasis from M5076 murine reticulosarcoma. Marginal inhibition was observed in the latter model, administering the drug 24 h after tumor cell injection. Efficacy was maintained in athymic mice, with 95 and 100% inhibition of lung metastasis from B16F10 melanoma and A375 human melanoma. The antimetastatic activity was confirmed in two models of spontaneous metastasis: in Lewis lung carcinoma implanted intramuscularly, daily intraperitoneal treatment from day 1 to 17 was associated with 77% inhibition of lung metastasis; on M5076 reticulosarcoma implanted intramuscularly, daily intraperitoneal treatment from day 1 to 14 prior to amputation of the tumor was associated with significant inhibition of liver metastasis (79%); conversely, daily intraperitoneal treatment from day 15 to 28 starting 1 day after amputation was marginally effective. The administered doses did not inhibit the growth of the primary tumor in both models. It is concluded that FCE 27266 is a novel, promising molecule, with significant efficacy on lung and liver metastases of murine and human origin; its mode of action is still under study and is probably exerted through inhibition of growth factors and cytokines influencing the different steps of angiogenesis and metastasis.
Assuntos
Antineoplásicos/farmacologia , Distamicinas/farmacologia , Distamicinas/uso terapêutico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Melanoma/patologia , Receptores de Fatores de Crescimento/metabolismo , Células 3T3 , Animais , Antineoplásicos/uso terapêutico , Ligação Competitiva , Linhagem Celular , Fatores de Crescimento Endotelial/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Células HL-60 , Humanos , Interleucina-1/metabolismo , Interleucina-8/metabolismo , Cinética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Linfocinas/metabolismo , Linfoma Difuso de Grandes Células B , Masculino , Melanoma/tratamento farmacológico , Melanoma/secundário , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Melanoma Experimental/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento/antagonistas & inibidores , Transplante Heterólogo , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
FCE 26644, or 7,7'-(carbonyl-bis[imino-N-methyl-4, 2 pyrrole carbonyl-imino(N-methyl-4,2-pyrrole)carbonyl-imino])-bis-(1,3- naphthalene)disulfonic acid, belongs to the newly synthesized class of sulfonated derivatives of distamycin A. FCE 26644 is a noncytotoxic molecule capable of inhibiting the binding of basic fibreblast growth factor (bFGF), platelet-derived growth factor (PDGF beta) and interleukin 1 (IL-7) to their receptors and to block bFGF-induced vascularization in vivo as well as neovascularization in the chorioallantoic membrane. FCE 26644 and suramin, a compound possessing the same terminal half-life (t1/2) in mice and, presumably, the same mode of action, inhibit the growth of solid murine tumors, M5076 reticulosarcoma, and MXT and S180 fibrosarcoma and are inactive against B16F10 melanoma. The activity of FCE 26644 was constantly observed at nontoxic doses, at variance with suramin. FCE 26644 was also found to maintain activity against M5076 resistant to cyclophosphamide and to be equally active against UV 2237 and UV 2237/ADR fibrosarcoma.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Distamicinas/farmacocinética , Distamicinas/uso terapêutico , Fibrossarcoma/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Animais , Ciclofosfamida/uso terapêutico , Esquema de Medicação , Resistência a Medicamentos , Feminino , Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Suramina/farmacocinética , Suramina/uso terapêuticoRESUMO
The effect of suramin on B16F10 melanoma lung colonies and M5076 reticulosarcoma liver metastasis formation was evaluated in C57B1/6 female mice. Single i.v. doses of 200 mg/kg suramin given 48 and 24 h prior to tumor cell injection significantly inhibited metastasis formation in both models, whereas the same treatment administered 24 h after cell injection was ineffective. A dose-response experiment in the B16F10 melanoma model showed that inhibition of lung colony formation was still significant with 50 mg/kg pretreatment, whereas a borderline effect was observed at 10 mg/kg. At the effective doses, the plasma and organ concentrations of suramin were far below those needed to exert significant in vitro cytotoxic or cytostatic effects on B16F10 and M5076 cells. Thus, in addition to the antineoplastic effect of suramin our results indicate a potential antimetastatic role for this compound.
Assuntos
Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/secundário , Suramina/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Suramina/farmacocinética , Células Tumorais CultivadasRESUMO
FCE 23762 is a new doxorubicin derivative obtained by appending a methoxymorpholinyl group at position 3' of the sugar moiety. The compound is greater than 80 times more potent than doxorubicin, it is highly lipophilic, and presents equivalent anti-tumour activity when administered by i.p., i.v. or oral route. The pattern of anti-tumour activity of FCE 23762 differs from that of doxorubicin in maintaining anti-tumour activity against two P388 murine leukaemia sublines resistant to doxorubicin and, although at borderline levels of efficacy, against LoVo human colon adenocarcinoma resistant to doxorubicin. FCE 23762 exhibits remarkable efficacy against MX-1 human mammary carcinoma, with most treated mice being cured both after i.v. and oral treatment. Anti-tumour activity was also observed against L1210 murine leukaemia and two sublines resistant to cis-platinum and melphalan, M5076 murine reticulosarcoma, MTV murine mammary carcinoma and N592 human small cell lung cancer.
Assuntos
Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Leucemia P388/tratamento farmacológico , Neoplasias Experimentais/tratamento farmacológico , Animais , Feminino , Humanos , Leucemia P388/patologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Transplante de Neoplasias , Neoplasias Experimentais/patologia , Transplante Heterólogo , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Solid tumor growth can be modulated through inhibition of vascularization elicited by angiogenic factors. With the objective to complex these factors, new derivatives of distamycin A were synthesized and evaluated in vitro [1] and in vivo for their ability, after i.v. administration, to inhibit bFGF-induced vascularization and the growth of M5076 murine reticulosarcoma implanted i.m. The tested compounds were able to block angiogenesis with inhibition values ranging between 70-100%. Moreover, they were found to be capable of inducing tumor inhibition with values ranging between 40% and 95% at non-toxic doses.