RESUMO
BACKGROUND: Leishmania (Viannia) guyanensis is believed to be the principal cause of cutaneous leishmaniasis (CL) in Suriname. This disease is treated with pentamidine isethionate (PI), but treatment failure has increasingly been reported. AIM: To evaluate PI for its clinical efficacy, to compare parasite load, and to assess the possibility of treatment failure due to other infecting Leishmania species. METHODS: Parasite load of patients with CL was determined in skin biopsies using real-time quantitative PCR before treatment and 6 and 12 weeks after treatment. Clinical responses were evaluated at week 12 and compared with parasite load. In parallel, molecular species differentiation was performed. RESULTS: L. (V.) guyanensis was the main infecting species in 129 of 143 patients (about 90%). PI treatment led to a significant decrease (P < 0.001) in parasite counts, and cured about 75% of these patients. Treatment failure was attributable to infections with Leishmania (Viannia) braziliensis, Leishmania (Leishmania) amazonensis and L. (V.) guyanensis (1/92, 1/92 and 22/92 evaluable cases, respectively). There was substantial agreement beyond chance between the parasite load at week 6 and the clinical outcome at week 12, as indicated by the κ value of 0.61. CONCLUSIONS: L. (V.) guyanensis is the main infecting species of CL in Suriname, followed by L. (V.) braziliensis and L. (L.) amazonensis. Furthermore, patient response to PI can be better anticipated based on the parasite load 6 weeks after the treatment rather than on parasite load before treatment.
Assuntos
Leishmania/isolamento & purificação , Leishmaniose Cutânea/tratamento farmacológico , Pentamidina/farmacologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Pele/parasitologia , Adolescente , Adulto , Idoso , Antiprotozoários/uso terapêutico , Feminino , Humanos , Injeções Intramusculares , Leishmania/efeitos dos fármacos , Leishmania/crescimento & desenvolvimento , Leishmania braziliensis/efeitos dos fármacos , Leishmania braziliensis/crescimento & desenvolvimento , Leishmania braziliensis/isolamento & purificação , Leishmania guyanensis/efeitos dos fármacos , Leishmania guyanensis/crescimento & desenvolvimento , Leishmania guyanensis/isolamento & purificação , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Masculino , Pessoa de Meia-Idade , Carga Parasitária/métodos , Pentamidina/administração & dosagem , Prevalência , Pele/efeitos dos fármacos , Pele/patologia , Suriname/epidemiologia , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Plant-based preparations are extensively used in Surinamese folk medicine for treating leishmaniasis, but often without a scientific rationale. AIM OF THE STUDY: To evaluate 25 Surinamese medicinal plants for their potential efficacy against leishmaniasis. MATERIALS AND METHODS: Concentrated plant extracts were evaluated for their effect on the viability of L. (V.) guyanensis AMC, L. (L.) major NADIM5, and L. (L.) donovani GEDII promastigotes, as well as intracellular amastigotes of L. (L.) donovani BHU814 in infected THP-1 cells. Selectivity was assessed by cytotoxicity against THP-1 cells. RESULTS: The only plant extract that showed potentially meaningful anti-leishmanial activity was that from Solanum lycocarpum that displayed mean IC50 values of about 51, 61, and <16 µg/mL against L. (V) guyanensis, L. (L) major, and L. (L) donovani promastigotes, respectively; about 374 µg/mL against L. (L) donovani amastigotes; and >500 µg/mL against THP-1 cells. The Bryophyllum pinnatum, Inga alba, and Quassia amara extracts displayed moderate to high IC50 values against promastigotes (about 51 to >500 µg/mL) and/or amastigotes (about 224 to >500 µg/mL) but were relatively toxic to THP-1 cells (IC50 values <16 to about 42 µg/mL). The remaining plant extracts exhibited in many cases IC50 values close to, around, or above 500µg/mL against promastigotes, amastigotes, and THP-1 cells. CONCLUSIONS: The S. lycocarpum preparation may be useful against leishmaniasis and may have a good safety index, warranting further investigations into its active constituents and mechanism(s) of action.
Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Extratos Vegetais/farmacologia , Plantas Medicinais , Solanum , Antiprotozoários/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Leishmania donovani/fisiologia , Leishmaniose/tratamento farmacológico , Extratos Vegetais/toxicidade , Suriname , Inquéritos e QuestionáriosRESUMO
PURPOSE: In this phase II and pharmacokinetic study, chronic, low-dose, oral etoposide was evaluated for its efficacy in patients with AIDS-related Kaposi's sarcoma who were not previously exposed to cytotoxic therapy. PATIENTS AND METHODS: Of 28 patients accrued for the study, 25 were assessable for toxicity and response. Twenty-four patients were male (homosexual or bisexual cases) and one patient was female (partner of a bisexual male). All patients were human immunodeficiency virus (HIV)-positive, New York University (NYU) disease stage IIB to IVB, and most exhibiting skin and lymph node and/or visceral disease. Median age was 33 years (range, 21 to 50), and median World Health Organization (WHO) performance status was 2 (range, 0 to 3). The patients received a mean number of six treatment courses (range, four to 27). Prior therapy included local/regional irradiation, immunotherapy (interferon-alpha), local resection, and/or cryotherapy. No prior cytotoxic therapy was allowed. Etoposide was administered at a schedule of 25 mg/m2 orally, twice a day for 7 days, every 2 weeks. Plasma concentrations of the drug were measured in six patients by a high-performance liquid chromatography (HPLC) method, after chloroform extraction using teniposide as internal standard. RESULTS: The overall response rate was 32% (two complete and six partial responses), and the median progression-free survival was 8 weeks (range, 4 to 27). Five patients (20%) had stable disease, while 12 cases (48%) did not respond. Patients without a history of opportunistic infections seemed to respond better. The regimen was well tolerated. The main toxic effects consisted of mild to moderate nausea and vomiting in approximately half of the cases, and WHO grodes 3 to 4 leukopenia and thrombocytopenia in eight of 25 (36%) and five of 25 (20%) of cases, respectively. However, only two patients had to discontinue treatment because of prolonged and severe neutropenia. No toxic deaths were documented. The pharmacokinetic analyses revealed the achievement of potentially therapeutic and lowly myelosuppressive plasma etoposide concentrations (2.1 micrograms/mL; range, 1.3 to 2.6) for a significant period of time, ie, for approximately 4.6 hours postdosing. CONCLUSION: At the schedule applied, etoposide shows significant objective antitumor activity in advanced AIDS-related Kaposi's sarcoma, and induces acceptable clinical toxicity. This apparent efficacy of the regimen could be a result of the prolonged maintenance of cytotoxic plasma concentrations of etoposide during each treatment course, and the absence of toxic peak levels of the drug. These results, together with the appreciable bioavailability of oral etoposide, make the regimen feasible for outpatient treatment of patients with advanced AIDS-related Kaposi's sarcoma. Further studies using the above-mentioned approach are warranted.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos Fitogênicos/uso terapêutico , Etoposídeo/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Adulto , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Esquema de Medicação , Etoposídeo/efeitos adversos , Etoposídeo/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Sarcoma de Kaposi/metabolismoRESUMO
We evaluated irinotecan (CPT-11) together with 5-fluorouracil (5-FU) for improved cell growth inhibition with respect to that by either agent alone in the human colon carcinoma cell lines SW620, HT-29 and SNU-C4. Cells were exposed for 24 h to each drug, as well as to various combinations and sequences of low, fixed doses of one drug with higher varying doses of the other, cultured for two more days in drug-free medium and then assessed for growth response with the sulphorhodamine B assay. Multiple drug effect analysis was used to evaluate the data, which were then related to the amount of DNA damage occurring in the cells which was determined by a fluorescence-enhancement assay for DNA unwinding. Cellular responses were also related to thymidylate synthase topoisomerase I and carboxyl esterase activities, which were assessed by a ligand-binding and a 3H-release assay; a DNA decatenation assay; and a spectrophotometric method, respectively. IC50 values for 5-FU alone in the SW620, HT29 and SNU-C4 cells were 15.3 +/- 0.8, 8.2 +/- 1.3 and 2.2 +/- 0.7 microM, respectively, and for CPT-11 2.0 +/- 0.9, 2.5 +/- 0.5 and 3.8 +/- 0.3 microM, respectively. The differential responses to 5-FU alone were possibly determined by differences in substrate affinity and conversion rate of thymidylate synthase (K(m) of approximately 7.5, 5.0 and 2.5 microM and V0 of approximately 800, 200 and 2400 microM/h, respectively). The comparable cellular responses to CPT-11 alone might be accounted for by the counterbalancing effects of differences in topoisomerase I (1, 1, and 1.5 arbitrary units, respectively) and carboxyl esterase activities (5055 +/- 1789, 4080 +/- 752, 1713 +/- 522 mU/mg, respectively). IC20 CPT-11 prior to 5-FU was additive to synergistic in SW620, HT-29 and SNU-C4 cells (CIs of 0.7 +/- 0.1). By contrast, pre-treatment with IC20 5-FU antagonised the CPT-11-mediated growth inhibition (CIs of 1.9 +/- 0.4, 1.7 +/- 1.1, 2.5 +/- 0.9, respectively). Simultaneous drug treatment did not produce more cell growth inhibition than either drug alone in the SW620 and the HT-29 cells, but was additive or antagonistic in the SNU-C4 cells (CIs of 1.1 +/- 0.3 and 2.2 +/- 1.4), depending on the ratio of the drugs. Increased DNA damage in the SW620 and HT-29 cells was only seen when IC20 CPT-11 preceded IC50 5-FU, resulting in approximately 40 and 25%, respectively, more lesions than for IC50 5-FU alone. In the SNU-C4 cells, not only such a treatment, but also simultaneous drug treatment produced (30 to 60%) more DNA damage than either drug alone. Our results show clear sequence-dependent antiproliferative effects and DNA damage formation by CPT-11 and 5-FU at combinations of low, fixed doses with higher, varying doses in cultured human colon carcinoma cells, and may be of relevance to the design of improved chemotherapeutic regimens in this disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Divisão Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Dano ao DNA , DNA de Neoplasias , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Células Tumorais CultivadasRESUMO
Treatment with 25 mumol/l D,L-buthionine-S,R-sulphoximine (BSO) for at least 24 h depleted glutathione (GSH) in human non-small cell lung (SW-1573), ovarian (A2780) and breast carcinoma (MCF-7) cell lines to about 20% of control, and was accompanied by a 2-fold potentiation of the cytotoxicity of etoposide, doxorubicin and cisplatin. Cellular etoposide, but not doxorubicin or cisplatin, concentrations were increased 2-fold due to decreased efflux. This occurred independently of the presence of BSO during 1 h of etoposide exposure, but required prolonged exposure to BSO (at least 24 h). Energy depletion as well as cotreatment, but not pretreatment, of the cells with daunomycin, doxorubicin, vinblastine or vincristine increased cellular etoposide accumulation. Treatment of control cells with verapamil caused similar changes in etoposide cytotoxicity and cellular pharmacokinetics as GSH depletion, but did not further increase etoposide cytotoxicity and accumulation in GSH-depleted cells. Etoposide efflux may have been inhibited, not because of (competitive) inhibition by BSO or disturbance of the energy required for this process, but probably because of plasma membrane alterations.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Etoposídeo/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Metionina Sulfoximina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias da Mama/metabolismo , Butionina Sulfoximina , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Sinergismo Farmacológico , Etoposídeo/farmacocinética , Feminino , Glutationa/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Metionina Sulfoximina/farmacologia , Neoplasias Ovarianas/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacos , Verapamil/farmacologiaRESUMO
We investigated the potential mechanisms of tamoxifen cytotoxicity in the U-373, U-138, and U-87 human glioblastoma cell lines, namely interference with protein kinase C (PKC) activity, the oestrogen receptor, and/or the production of transforming growth factor beta 1 (TGF-beta 1). We further examined the effects of tamoxifen on the cytotoxicity exerted by gamma-radiation, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and etoposide in this cell line panel. Thus, the cells were treated for 4 days with tamoxifen, gamma-radiation, purified recombinant human TGF-beta 1 (rhTGF-beta 1), BCNU, or etoposide, either alone or at certain combinations. Cellular responses were evaluated with the sulphorhodamine B assay, as well as by multiple drug effect analysis, and related to PKC activities in particulate and cellular fractions; cellular oestrogen receptor contents; and the influence of rhTGF-beta 1 on cell growth. Tamoxifen inhibited cell proliferation as well as the phosphorylation capacity of the particulate, but not of the cytosolic fractions dose-dependently, at comparable kinetics, and at IC50 values of approximately 15 microM. At these concentrations, tamoxifen acted synergistically with gamma-radiation (4- to 6-fold) and additively with BCNU (approximately 2-fold), but did not affect etoposide cytotoxicity. The cells were negative to immunostaining for the oestrogen receptor, and rhRGF-beta 1 did not influence their growth up to 100 nm. Our data suggest that tamoxifen can sensitise cultured glioblastoma cells not to etoposide but to gamma-radiation and BCNU, possibly through interference with membrane PKC, supporting its evaluation in experimental protocols for primary malignant gliomas.
Assuntos
Antineoplásicos/uso terapêutico , Carmustina/uso terapêutico , Etoposídeo/uso terapêutico , Raios gama , Glioblastoma/tratamento farmacológico , Proteína Quinase C/antagonistas & inibidores , Tamoxifeno/uso terapêutico , Fator de Crescimento Transformador beta/farmacologia , Divisão Celular , Sinergismo Farmacológico , Humanos , Imuno-Histoquímica , Receptores de Estrogênio/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos da radiaçãoRESUMO
In this report, the types of DNA damage introduced by the ortho-quinone and the semiquinone free radical of 4'-demethylepipodophyllotoxin-9-(4-6-O-ethylidene-beta-D- glucopyranoside) (etoposide) and their relevance for the inactivation of single-stranded (ss) and double-stranded (ds) replicative form (RF) phi X174 DNA have been examined in vitro. The ortho-quinone yielded in both ss and ds DNA only chemical adducts, of which on the average about 1 out of 3 and 1 out of 12 per DNA molecule led to inactivation of ss or RF phi X174 DNA, respectively. The semi-quinone free radical, on the other hand, generated both frank and alkali-labile strand-breaks in ss and in ds DNA which, however, did not contribute significantly to DNA inactivation. The radical introduced, in addition, chemical DNA adducts. Unlike the ortho-quinone adducts, however, each of the semi-quinone adducts was lethal in ss phi X174 DNA, while more than 40 were required for the inactivation of RF DNA. The excision repair system of Escherichia coli did not operate on semi-quinone-modified RF DNA but removed about half of the ortho-quinone adducts [van Maanen JMS, Lafleur MVM, Mans DRA, van den Akker E, de Ruiter C, Koostra PR, Pappie D, de Vries J, Retèl J and Pinedo HM, Biochem Pharmacol 37: 3579-3589, 1988]. When ortho-quinone-modified ss or ds DNA was subjected to a post-alkaline treatment, the adducts remained stably bound to the DNA and the degree of biological inactivation was not influenced. In contrast, post-alkaline treatment removed about 70 and 60% of the semi-quinone adducts from ss and ds DNA, respectively, which, in the case of ss phi X174 DNA, resulted in a partial restoration of the biological activity. It is concluded that the ortho-quinone and the semi-quinone free radical of etoposide produce different types of damage in DNA which have different effects on the biological activity.
Assuntos
DNA de Cadeia Simples/metabolismo , DNA/metabolismo , Etoposídeo/metabolismo , DNA/efeitos dos fármacos , Dano ao DNA , DNA de Cadeia Simples/efeitos dos fármacos , DNA Viral/efeitos dos fármacos , DNA Viral/metabolismo , Etoposídeo/efeitos adversos , Radicais Livres/metabolismo , Concentração de Íons de Hidrogênio , Quinonas/metabolismoRESUMO
Etoposide [4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta- D-glucopyranoside)] can be metabolized to DNA-inactivating catechol, ortho-quinone and semi-quinone free radical derivatives which may contribute to its cytotoxicity. In this paper, we examined in vitro whether glutathione (GSH), which is known to react easily with quinoid compounds, could interact with the active etoposide intermediates and in this way influence the cytotoxicity of the parent compound. To this end, reactions of GSH with the etoposide intermediates were studied, using HPLC and ESR measurements, together with the effects of GSH on the biological inactivation of single-stranded (ss) and double-stranded (RF) phi X174 DNA by these compounds. From the results it could be determined that: (a) GSH does not react with the catechol and, as a consequence, has no effect on the reaction of this intermediate of etoposide with ss and RF phi X174 DNA; (b) GSH reacts with the ortho-quinone most likely by formation of a conjugate and by two-electron reduction to the catechol, resulting in a partial protection of ss and RF phi X174 DNA against inactivation by this species; and (c) GSH protects ss phi X174 DNA against inactivation by the semi-quinone free radical of etoposide probably by conjugation with this species.
Assuntos
Catecóis/química , DNA/química , Etoposídeo/química , Glutationa/química , Quinonas/química , Bacteriófago phi X 174/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , DNA de Cadeia Simples/química , Espectroscopia de Ressonância de Spin Eletrônica , Radicais Livres , Glutationa/farmacologia , Fenóis/químicaRESUMO
We have studied the effects of the recently reported two new metabolites of the antitumor agent VP-16-213, the ortho-dihydroxy derivative or catechol and the ortho-quinone, on the biological activity of single-stranded and double-stranded phi X174 DNA, the binding of the metabolites to calf thymus DNA and the conversion of the catechol into the ortho-quinone. Evidence was obtained for the oxidation of the catechol into the ortho-quinone and for the fact that the ortho-quinone is the metabolite of VP-16-213 responsible for its binding to rat liver microsomal proteins. The catechol and ortho-quinone of VP-16-213 were found to bind 7-9 times more strongly to calf thymus DNA than VP-16-213 itself. In contrast to the parent compound VP-16-213, the catechol as well as the ortho-quinone inactivated both single-stranded (ss) and double-stranded (RF) biologically active phi X174 DNA. The mean T37-values for inactivation of ss and RF phi X174 DNA by 2.2 x 10(-4)M catechol at 37 degrees and pH 7.4 were 96 and 640 min, respectively. Reduction of the ortho-quinone by NADPH cytochrome P-450 reductase resulted in formation of the catechol. The system ortho-quinone/NADPH cytochrome P-450 reductase inactivated ss phi X174 DNA with a mean T37-value of 454 min, and this inactivation was inhibited by DMSO. The mean T37-value for inactivation of ss phi X174 DNA by 1.8 x 10(-4) M ortho-quinone at 37 degrees and pH 4.0 was 24 min. The chemical stability of the ortho-quinone and the extent of inactivation of ss phi X174 DNA by the ortho-quinone were both pH-dependent: at higher pH the ortho-quinone was less stable and gave less inactivation of DNA. The aqueous decomposition product(s) of the ortho-quinone formed at pH 7.4 inactivated ss phi X174 DNA with a mean T37-value of 175 min. The rate of inactivation of RF phi X174 DNA by the ortho-quinone at pH 4.0 was twice as low as the rate of inactivation of ss phi X174 DNA: T37 = 49 min. When using excision repair deficient E. coli mutants (uvrA- or uvrC-), a higher inactivation of RF phi X174 DNA was found: T37 = 29 min for uvrA- E. coli, indicating that a part of the DNA damage introduced by the incubation with ortho-quinone is removed by excision repair.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Catecóis/farmacologia , DNA Viral/efeitos dos fármacos , Etoposídeo/metabolismo , Quinonas/farmacologia , Animais , Bacteriófago phi X 174/efeitos dos fármacos , Dano ao DNA , DNA de Cadeia Simples/efeitos dos fármacos , DNA Viral/metabolismo , Etoposídeo/farmacologia , Concentração de Íons de Hidrogênio , Masculino , Oxirredução , Ligação Proteica , Ratos , Ratos EndogâmicosRESUMO
Two patients presenting with malignant meningitis resulting from small-cell carcinoma of the lung and with lymphoblastic leukemia, respectively, were treated by intrathecal administration of etoposide. In both cases, this treatment was well tolerated and produced relief of the central nervous system symptoms. Pharmacokinetic data showed that cerebrospinal fluid drug levels of up to 5.2 micrograms/ml were achieved, which were considerably higher than those obtained after i.v. administration of high-dose etoposide.
Assuntos
Etoposídeo/administração & dosagem , Meningite/tratamento farmacológico , Adulto , Carcinoma de Células Pequenas/líquido cefalorraquidiano , Carcinoma de Células Pequenas/complicações , Carcinoma de Células Pequenas/tratamento farmacológico , Etoposídeo/líquido cefalorraquidiano , Etoposídeo/farmacocinética , Estudos de Viabilidade , Humanos , Injeções Espinhais , Neoplasias Pulmonares/líquido cefalorraquidiano , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Meningite/líquido cefalorraquidiano , Meningite/etiologia , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
This phase II trial was conducted to evaluate the percentage of objective responses and the toxicity profile of combination doxorubicin (Adriamycin) and paclitaxel (Taxol) with granulocyte colony-stimulating factor as first-line therapy for patients with metastatic breast cancer (MBC) not previously exposed to anthracycline-containing regimens. Patients with measurable, visceral-dominant MBC and a performance status of 0 to 2 were included in the study. Doxorubicin 60 mg/m2 was administered as a short intravenous infusion, followed by paclitaxel 250 mg/m2 as a 3-hour intravenous infusion on day 1. Granulocyte colony-stimulating factor 5 micrograms/kg/d was given prophylactically as a subcutaneous injection from day 2 until granulocyte recovery to > or = 1,500/mm3. Treatment was repeated every 21 days for a maximum of six courses. Dose reductions (to doxorubicin 50 mg/m2 and paclitaxel 175 mg/m2) and/or treatment delay were applied in case of severe toxicity. All 25 women who entered were evaluable for response and toxicity. The main grade 3/4 toxicities observed were leukopenia, thrombocytopenia, and mucositis. Alopecia occurred in all patients. No clinically relevant cardiovascular toxicity was observed. Severe myelosuppression and/or mucositis necessitated dose reductions at courses 2 or 3 in all but one patient. The complete response rate was 28%, and the partial response rate was 52% for an overall objective response rate of 80%. Median progression-free survival for complete responders was 11 months (range, 3 to 24 months), while the progression-free survival was 7+ months (range 2 to 14+ months) for partial responders and 5 months (range, 3 to 9 months) for nonresponders. This combination produces a high objective response rate in women with MBC, but dose reductions were necessary in almost all cases. Toxicity was manageable after dose reduction, allowing patients to be re-treated for two to six courses without life-threatening toxicity or toxic deaths. Unfortunately, the duration of response was limited even among complete responders. Further trials of this combination in patients with MBC should explore improvements in this study regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Progressão da Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Pessoa de Meia-Idade , Neutropenia/prevenção & controle , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , SobrevidaRESUMO
The purpose of this study was to examine the antitumor activity, toxic effects, and plasma pharmacokinetics of fractionated doses of oral etoposide aiming at the achievement of prolonged safe and active plasma drug levels in patients with AIDS-related Kaposi sarcoma (KS). This was designed as a phase II trial in which consecutive patients with progressing AIDS-KS after at least 3 months of active antiretroviral therapy received oral etoposide at the dose of 20 mg/m2 every 8 hours daily for 7 days every 21 days, with the study of its plasma pharmacokinetics. Eligible patients were 18 to 60 years old, with a histopathologically confirmed diagnosis of AIDS-related KS, human immunodeficiency virus-positive test, progressing after at least 3 months of active antiretroviral therapy, World Health Organization (WHO) performance status 0 to 3, New York University staging IIA or greater, no active infection except oral candidiasis, normal bone marrow, liver, and renal function, and who signed an informed consent. Objective tumor responses were evaluated after at least one full treatment course according to a modified WHO criteria, and toxicity was evaluated weekly and graded using the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) criteria. For the pharmacokinetic study, plasma was obtained from patients during the first drug administration immediately before and at various time points thereafter. Etoposide was measured after extraction from plasma by a standard high-performance liquid chromatography. Twenty-one patients were accrued for the study, and 18 of them met the eligibility criteria. They were all men, with median age of 36 years old (range: 25-50 years), median WHO performance status 0 (range: 0-3) median CD4+ count (cells/mm3) 67 (range: 8-443), prior AIDS diagnosis in 10 of 18 cases, NYU staging IIA (1 patient), IIB (1), IIIA (7), IIIB (1), IVA (4), and IVB (4) sites of disease: mucocutaneous only (5), mucocutaneous/lymph nodes (5), mucocutaneous/lung (5) and mucocutaneous/lymph nodes/lung (2); and prior cytotoxic treatment in two patients. Seventy-two percent of cases presented some form of toxic effect (NCI-CTC). Leukopenia was documented in 50% of cases, anemia occurred in 61%, whereas thrombocytopenia was documented in 17% of the patients. The main nonhematologic toxicities were nausea and vomiting in 17% of cases and alopecia in 44%. The overall objective response rate was 83%, with 2 complete remissions documented (11%). The median duration of responses was 12 weeks (range: 3-45 weeks). The median t1/2 of etoposide in plasma was 4.11 hours (range: 1.95-9.64), area under the curve was 13.51 microg/h/ml (range: 7.12-24.42), Cmax was 2.17 microg/ml (1.40-4.41), tmax (1.00-2.00), mean residence time 4.62 hours (range: 3.75-5.20 hours), CIt (total clearance) 3.13 l/m2/h (range: 1.49-5.20 l/m2/h), Vd 13.08 l/m2 (range: 6.23-19.65 l/m2), and the median etoposide plasma concentration time greater than 1 microg/ml was 3.69 hours (range: 1.00-6.80 hours). The use of fractionated oral daily doses of etoposide produced significant antitumor activity with manageable clinical toxicity in the individuals with AIDS-KS included in this trial. This more favorable therapeutic index of etoposide could be due to the achievement of more sustained plasma levels of the drug within safe but active concentrations.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Etoposídeo/administração & dosagem , Sarcoma de Kaposi/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/complicações , Administração Oral , Adulto , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Área Sob a Curva , Esquema de Medicação , Etoposídeo/sangue , Etoposídeo/farmacocinética , Etoposídeo/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma de Kaposi/complicaçõesRESUMO
Colorectal cancer is one of the most frequent malignancies in humans and an important cause of cancer death. Metastatic colorectal cancer remains incurable with available systemic therapeutic options. The most active cytotoxic drug against this malignancy, the antimetabolite 5-fluorouracil, was developed more than forty years ago, and as a single agent produces responses in only 10 to 15% of patients which in general last less than one year. Efforts to ameliorate these poor results resulted in the 5-fluorouracil/leucovorin combination, which enhances response rates about two-fold, without, however, significantly improving survival rates. The recent emergence of a handful of new 5-fluorouracil analogues and folate antagonists, as well as the topoisomerase I inhibitor irinotecan, and the third-generation platinum compound oxaliplatin, is likely to alter this gloomy scenario. These agents are at least as effective as 5-fluorouracil in patients with advanced colorectal carcinoma, both untreated and previously treated with 5-fluorouracil-based regimens. This has led to the approval of irinotecan as second-line treatment for 5-fluorouracil-refractory disease, while the use of oxaliplatin has been suggested for patients having a defective 5-fluorouracil catabolism. Recently, FDA approved the combination of irinotecan with 5-fluorouracil and leucovorin for first-line treatment of advanced colon cancer. Based on the synergistic preclinical antitumor effects of some of these agents, their meaningful single-agent activity, distinct mechanisms of cytotoxicity and resistance, and only partially overlapping toxicity profiles, effective combination regimens are now being developed, which are likely to lead to a new, more hopeful era for patients suffering from advanced colorectal carcinoma.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/metabolismo , Camptotecina/farmacologia , Ensaios Clínicos como Assunto , Neoplasias Colorretais/metabolismo , Quimioterapia Combinada , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Irinotecano , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Compostos Organoplatínicos/metabolismo , Compostos Organoplatínicos/farmacologia , OxaliplatinaRESUMO
The methanol extract of fresh leaves of Solanum melongena L. (Solanaceae) was evaluated for its capacity to alter the tone of isolated, pre-contracted guinea pig tracheal chains, as well as for its possible mechanism(s) of action. Using serial dilutions between 0.0025 and 2.5 mg/mL, the extract was found to cause a dose-dependent increase in the force of muscle contraction. The EC(50) value was 0.46 +/- 0.01 mg/mL. The concomitant use of acetylcholine 10(-5) M did not significantly affect the force of contraction induced by the extract. Histamine 10(-5) M added at about 40% to, and salbutamol 10(-6) M antagonized by about 30% its constrictive effect. Chlorpheniramine 10(-6) M, propanolol 10(-5) M, and nifedipine 10(-6) M did not significantly influence the extract-induced force of contraction, but atropine 3 x 10(-7) M reduced it by approximately 60%. These data suggest that the Solanum melongena extract exerted a bronchospasmogenic rather than a bronchospasmolytic effect, probably through muscarinic receptor stimulation.
Assuntos
Contração Muscular/efeitos dos fármacos , Solanaceae , Traqueia/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Relação Dose-Resposta a Droga , Cobaias , Técnicas In Vitro , Contração Muscular/fisiologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Folhas de Planta , Traqueia/fisiologiaRESUMO
BACKGROUND: In a phase II study, topotecan was evaluated for response and toxicity in patients with advanced pancreatic carcinoma at the schedule of 0.7 mg/m2/day q 21 days q 28 days. METHODS: Responses were assessed after at least 2 courses using WHO criteria, and toxicity was evaluated after each course according to the CTC-NCI standards. Between December 1995 and September 1997, 15 assessable patients (median age, 55 years; range, 36-74; median ECOG performance, 1; range, 0-3) were included in the study. All had biopsy-proven and measurable disease, a life-expectancy of at least 3 months, and normal bone marrow, liver, and renal function. None of the patients had undergone prior cytotoxic or radiation therapy, and 10 were initially treated by surgery. Twenty-five cycles were assessable for toxicity. Plasma was collected from 7 patients who had received a total of 10 cycles and was, after extraction with methanol at -20 degrees C, analyzed for total topotecan by an HPLC method. The thus determined steady-state concentrations were assessed for their capacity to affect growth and DNA integrity in the BxPC-3 human pancreatic carcinoma cell line after 21 days of continuous exposure. For these purposes, we used a sulforhodamine B staining assay, and agarose gel electrophoresis, respectively. RESULTS: Grades 3-4 leukopenia, thrombocytopenia, granulocytopenia, and anemia occurred in 8, 6, 8 and 8 cycles, respectively. Other mild to moderate side effects (grades 1-2) included malaise, nausea and vomiting, anorexia, and alopecia. No objective tumor response was documented. HPLC analysis of patients' plasma showed the attainment of constant steady-state levels of 1.0+/-0.1 ng/mL during the entire infusion period. At such a concentration, topotecan did not significantly affect growth or DNA integrity in the BxPC-3 cells. Fifty percent cell growth inhibition and appreciable oligonucleosomal DNA fragmentation were only evident with 21 days topotecan > or = 50 ng/mL. CONCLUSIONS: Our data suggest that the lack of clinical activity of 0.7 mg/m2 daily topotecan for 21 days q 28 days in patients with advanced pancreatic carcinoma might be partially attributed to the achievement of non-tumoricidal plasma drug concentrations.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Topotecan/farmacologia , Adenocarcinoma/patologia , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Falha de TratamentoRESUMO
AIMS AND BACKGROUND: To evaluate the response rate, toxicity and survival of patients with AIDS-related Kaposi's sarcoma (AIDS-KS) treated in a phase II clinical trial of pentosan polysulpate (PPS), an inhibitor of basic-fibroblast growth factor (b-FGF) which blocks the growth of Kaposi's sarcoma cells both in culture and in animal models. PATIENTS AND METHODS: Between March 1992 and March 1994 16 homosexual males with histopathologically confirmed AIDS-KS were accrued for this phase II clinical trial. PPS was administered at the dose of 25 mg/m2 q6 hrs at day 1, followed by 25 mg/m2 q12 hrs daily by a subcutaneous injection. The number of patients to be included in the trial was calculated according to the two-stage Gehan method. Toxicity was graded according to the NCl Common Toxicity Criteria, while responses were evaluated according to the WHO Criteria adapted for KS lesions. Patients were all homosexual males, median age 35 (27-43) years, performance status (WHO) 1 (0-2), NYU stage II-IV and prior therapy included vincristine and etoposide (3 cases), local irradiation (4 cases) and megestrol acetate (2 cases). Concomitant AZT (zidovudine) was given to 3 patients, while DDI (dideoxyinosine) was administered in one case. RESULTS: A median of 5 (3-11) weeks of therapy was administered to the patients. Pain at the injection site and low grade fever were the only toxicities observed. Drug-related effects on coagulation parameters or thrombocytopenia were not observed in the trial. One objective response (6%) was documented, which lasted for 9 weeks, while stable disease was observed in three patients, lasting for 11, 9 and 5 weeks, respectively. CONCLUSION: This is the first observation of objective antitumor activity with a b-FGF inhibitor in patients with AIDS-KS. Considering it novelty and the lack of significant toxicity, the authors suggest that this experimental approach deserves further evaluation.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos/uso terapêutico , Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Poliéster Sulfúrico de Pentosana/uso terapêutico , Sarcoma de Kaposi/virologia , Síndrome da Imunodeficiência Adquirida/etiologia , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Esquema de Medicação , Homossexualidade Masculina , Humanos , Masculino , Poliéster Sulfúrico de Pentosana/administração & dosagem , Poliéster Sulfúrico de Pentosana/efeitos adversos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Throughout medical history, plant products have been shown to be valuable sources of novel anti-cancer drugs. Examples are the VINCA: alkaloids, the taxanes, and the camptothecins, derived from the Madagscan periwinkle plant Catharantus roseus, the Pacific yew Taxus brevifolia, and the Chinese tree Camptotheca acuminata, respectively. For this reason, the South-American Office for Anti-Cancer Drug Development has implemented a large-scale project of acquisition and testing of compounds isolated from South American medicinal plants. The species are selected on the basis of a potentially useful phytochemical composition by consulting ethnopharmacological, chemosystemic, and ecological information. The collected samples are dried and first extracted with an organic solvent, then with distilled water. These crude extracts are evaluated at a concentration of 50 microg/ml for antiproliferative activity against one cell line. Extracts that significantly inhibit the growth of the cells (>/=50%) at relatively low concentrations (=50 microg/ml) are submitted to the more comprehensive disease-oriented screen of the U.S. National Cancer Institute. In parallel, these samples are further purified by bioassay-guided purification, involving repeated fractionation by diverse chromatography methods. If the active substance is expected to represent a novel structure, it is identified by appropriate chemical techniques, mechanistic studies are performed with a wide diversity of tumor models and laboratory techniques, and efforts are undertaken for the synthesis of potentially more useful analogs.
Assuntos
Antineoplásicos Fitogênicos , Etnofarmacologia , Plantas Medicinais , Antineoplásicos Fitogênicos/química , Brasil , Conservação dos Recursos Naturais , Ensaios de Seleção de Medicamentos Antitumorais , HumanosRESUMO
In the present study the effect was tested of reduced neopterin (RN) on the methylating capacity of the pineal gland of adult, male golden hamsters, housed under standardized conditions throughout the year. An effect of RN on the synthesis of a number of methylated compounds was, indeed, demonstrated. It is concluded that RN not only influences the indole metabolism by being the cofactor of tryptophan-hydroxylase, but that it might be involved in the regulation of other enzymes as well. Incubation with RN was most effective at the end of the light period. As this is also the time at which melatonin (aMT) injections cause gonadal atrophy in hamsters, kept under long photoperiod, this time of the day may be very important for aMT synthesis. A season-bound influence of RN was also demonstrated. The effect of RN was stimulatory in September, November and January for 5-methoxy-tryptamine (MT) and in November for 5-methoxytryptophan (MW) synthesis, but inhibitory in July. Furthermore, the effect of RN was stimulating for 5-methoxyindole-3-acetic acid (MA) and aMT in September, while the influence in the other months tested was absent or slightly inhibiting. These results suggest that the influence of RN in the pineal may be regulatory to various enzymes of the indole metabolism.
Assuntos
Biopterinas/farmacologia , Indóis/metabolismo , Glândula Pineal/metabolismo , Pteridinas/farmacologia , 5-Hidroxitriptofano/biossíntese , Animais , Biopterinas/análogos & derivados , Cricetinae , Indóis/biossíntese , Masculino , Melatonina/biossíntese , Mesocricetus , Metilação , Neopterina , Triptofano/metabolismoRESUMO
Until now the day/night and seasonal rhythmicity in the synthesis of 5-methoxyindoles (MI) is thought to be regulated by environmental factors, especially photoperiod and temperature. Endogenous factors are also implicated in the generation of N-acetyltransferase and hydroxyindole-O-methyltransferase activity rhythms. In the present experiments seasonal rhythmicity in the synthesis of MI in the pineal gland was investigated in hamsters kept under the same artificial conditions throughout the year. Though the environmental conditions were the same, day/night and seasonal rhythmicity in the production of MI in the pineal were observed indicating the existence of endogenous factors influencing the rhythmicities. In November, most of the MI showed the highest synthesis, MA and ML excepted, which were especially produced in July and September. The results obtained sustain the hypothesis that aMT is synthesized from MT rather than from aHT. Moreover, the rhythmicities in aMT synthesis are not identical to those found in aMT concentration as described in the literature. This indicates that synthesis and concentration of a compound are not comparable. At the end of the light period, when aMT injections have an antigonadotropic effect, a peak of aMT synthesis was always present. Although MI synthesis showed seasonal rhythmicity, no reproductive cycle occurred in the hamsters. At present, the concept that the pro- and/or antigonadal effects of the pineal are mediated by aMT seems to be the most acceptable. The present results, however, indicate that aMT and perhaps other MI, often regarded as factors influencing gonadal growth in golden hamsters, are not the only factors involved.
Assuntos
Indóis/biossíntese , Glândula Pineal/metabolismo , Estações do Ano , 5-Hidroxitriptofano/metabolismo , 5-Metoxitriptamina/biossíntese , Animais , Cricetinae , Masculino , Melatonina/biossíntese , Mesocricetus , Triptofano/análogos & derivados , Triptofano/biossínteseRESUMO
Seasonal rhythmicity in the reproductive cycle was demonstrated in golden hamsters exposed to natural conditions. Testes regress in weight and function from October up to April. Reproductive functional testes are found in June. Although less marked, body weight also shows seasonal variations: a retarded growth in winter and early spring. In the pineal gland of these animals diurnal and seasonal rhythmicity was found in the synthesis of various MI. It has been concluded that rhythms in the pineal of animals kept under artificial conditions are often more pronounced as compared to those in hamsters kept under natural conditions. Melatonin (aMT) synthesis was observed during the day as well as during the night. A certain resemblance in patterns of day/night rhythms as to aMT and 5-methoxytryptamine (MT) production was reported suggesting a physiological role of MT. To facilitate the discussion on seasonal rhythmicity the average synthesis per day of the 5-methoxyindoles (MI) was calculated. During the period of gonadal regression in fall and early winter, MT and aMT, which are both generally accepted as pineal antigonadotropins, showed opposite patterns in rhythms of mean synthesis; MT decreased but aMT increased from October up to December. It was suggested that under natural conditions MT may induce and aMT maintain gonadal atrophy. Furthermore, also other MI showed relatively high amounts of production, at least in November. The period of recrudescence was characterized by a high synthesis of 5-methoxytryptophan (MW), 5-methoxytryptophol (ML) and O-acetyl-5-methoxytryptophol (aML). This confirms an earlier suggestion that aML can be considered a counter-antigonadotropic substance of the hamster pineal gland. Therefore it was concluded that, apart from MT and aMT, also other MI may be of physiological importance in the regulation of gonadal atrophy.