RESUMO
PURPOSE: Busulfan-melphalan high-dose chemotherapy followed by autologous stem cell transplantation is an essential consolidation treatment of high-risk neuroblastoma in children. Main treatment limitation is hepatic veno-occlusive disease, the most severe and frequent extra-hematological toxicity. This life threatening toxicity has been related to a drug interaction between busulfan and melphalan which might be increased by prior disturbance of iron homeostasis, i.e. an increased plasma ferritin level. METHODS: We performed an experimental study of busulfan and melphalan pharmacodynamic and pharmacokinetics in iron overloaded mice. RESULTS: Iron excess dramatically increased the toxicity of melphalan or busulfan melphalan combination in mice but it did not modify the clearance of either busulfan or melphalan. We show that prior busulfan treatment impairs the clearance of melphalan. This clearance alteration was exacerbated in iron overloaded mice demonstrating a pharmacokinetic interaction. Additionally, iron overload increased melphalan toxicity without altering its pharmacokinetics, suggesting a pharmacodynamic interaction between iron and melphalan. Based on iron homeostasis disturbance, we postulated that prior induction of ferritin, through Nrf2 activation after oxidative stress, may be associated with the alteration of melphalan metabolism. CONCLUSION: Iron overload increases melphalan and busulfan-melphalan toxicity through a pharmacodynamic interaction and reveals a pharmacokinetic drug interaction between busulfan and melphalan.
Assuntos
Bussulfano/metabolismo , Bussulfano/toxicidade , Sobrecarga de Ferro/metabolismo , Melfalan/metabolismo , Melfalan/toxicidade , Animais , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/toxicidade , Interações Medicamentosas/fisiologia , Sobrecarga de Ferro/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
PURPOSE: Intravitreal melphalan is emerging as an effective treatment for refractory vitreous seeds in retinoblastoma, but there is limited understanding regarding its toxicity. This study evaluates the retinal and systemic toxicity of intravitreal melphalan in retinoblastoma patients, with preclinical validation in a rabbit model. DESIGN: Clinical and preclinical, prospective, cohort study. PARTICIPANTS: In the clinical study, 16 patient eyes received 107 intravitreal injections of 30 µg melphalan given weekly, a median of 6.5 times (range, 5-8). In the animal study, 12 New Zealand/Dutch Belt pigmented rabbits were given 3 weekly injections of 15 µg of intravitreal melphalan or vehicle to the right eye. METHODS: Electroretinogram (ERG) responses were recorded in both humans and rabbits. For the clinical study, ERG responses were recorded at baseline, immediately before each injection, and at each follow-up visit; 82 of these studies were deemed evaluable. Median follow-up time was 5.2 months (range, 1-11). Complete blood counts (CBCs) were obtained on the day of injection at 46 patient visits. In the animal study, ERG responses were obtained along with fluorescein angiography, CBCs, and melphalan plasma concentration. After humane killing, the histopathology of the eyes was evaluated. MAIN OUTCOME MEASURES: For the clinical study, we measured peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation with comparisons between ERG studies before and after intravitreal melphalan. For the animal study, we collected ERG parameters before and after intravitreal melphalan injections with histopathologic findings. RESULTS: By linear regression analysis, over the course of weekly intravitreal injections in retinoblastoma patients, for every additional injection, the ERG amplitude decreased by approximately 5.8 µV. The ERG remained stable once the treatment course was completed. In retinoblastoma patients, there were no grade 3 or 4 hematologic events. One week after the second injection in rabbits, the a- and b-wave amplitude declined significantly in the melphalan treated eyes compared with vehicle-treated eyes (P<0.05). Histopathology revealed severely atrophic retina. CONCLUSIONS: Weekly injections of 30 µg of melphalan can result in a decreased ERG response, which is indicative of retinal toxicity. These findings are confirmed at an equivalent dose in rabbit eyes by ERG measurements and by histopathologic evidence of severe retinal damage. Systemic toxicity with intravitreal melphalan at these doses in humans or rabbits was not detected.
Assuntos
Antineoplásicos Alquilantes/toxicidade , Melfalan/toxicidade , Inoculação de Neoplasia , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Contagem de Células Sanguíneas , Criança , Pré-Escolar , Avaliação Pré-Clínica de Medicamentos , Eletrorretinografia , Feminino , Angiofluoresceinografia , Humanos , Lactente , Injeções Intravítreas , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Estudos Prospectivos , Coelhos , Análise de Regressão , Neoplasias da Retina/fisiopatologia , Retinoblastoma/fisiopatologia , Corpo Vítreo/patologiaRESUMO
Melatonin (MLT) is a natural oncostatic factor of the human body as well as an antioxidant thus protects the nuclear DNA from oxidative damage. It also has the ability to reduce the side effects of various drugs when used as a combination therapy. The anti-neoplastic agent melphalan (MEL), which encompasses a number of side effects, is a strong alkylating agent and a potent inducer of sister chromatid exchanges (SCEs). The aim of the current in vitro study was to investigate the ability of MLT to reduce the genotoxic effect of MEL on normal human cultured peripheral lymphocytes. Cells were treated with both agents at various concentrations (MLT 100, 200 and 400 microM and MEL 330, 490 and 650 nM) and incubated for 72 h prior harvesting. The levels of cytostaticity, cytotoxicity and genotoxicity were qualitatively evaluated using the proliferation rate index, the mitotic index and the SCE methodology, respectively. Our results demonstrated the protective effect of MLT on cells treated with MEL in vitro. The greatest protective effect of MLT at 100 and 400 microM was illustrated against 330 nM of MEL in comparison with all other doses of MEL. These observations imply that MLT may be proved useful in reducing some of the toxic effects associated with certain classes of chemotherapeutic agents and other chemical and physical mutagens and carcinogens, acting both as an antioxidant-radical scavenger and a protective mechanism against cellular damage due to exposure to free radical-producing agents. It is essential to investigate substances with protective properties which are normally produced from the human body.
Assuntos
Antineoplásicos Alquilantes/antagonistas & inibidores , Antioxidantes/farmacologia , Citoproteção , Dano ao DNA , Melatonina/farmacologia , Melfalan/antagonistas & inibidores , Antineoplásicos Alquilantes/toxicidade , Células Cultivadas , Humanos , Linfócitos/efeitos dos fármacos , Melfalan/toxicidadeRESUMO
We retrospectively evaluated the outcome of reduced-intensity conditioning (RIC) followed by allogeneic hematopoietic stem cell transplantation (HCT) in 43 patients with myelodysplastic syndrome (MDS) or AML arising from MDS. All patients received fludarabine plus melphalan followed by an allogeneic HCT from an HLA-identical sibling (SIB: n=19) or unrelated donor (MUD: n=24). Median age was 58 years (range: 30-71). Diagnoses at transplantation were RA (n=8), RARS (n=1), RAEB (n=13), RAEB-T (n=6), or AML arising from MDS (n=15). Of 28 patients with MDS, two patients had low, 10 had intermediate-1, nine had intermediate-2 and seven had high-risk MDS by IPSS criteria. All patients initially engrafted with the median neutrophil recovery of 15 days (range: 9-27). The 2-year overall survival, disease-free survival, relapse and transplant-related mortality were 53.5% (CI 45.2-61.1), 51.2% (CI 43.3-58.5), 16.3% (CI 7.9-30.7) and 35.2% (26.4-45.7), respectively. Grade II-IV acute graft-versus-host disease occurred in 27 (63%) patients. There was no significant survival difference between SIB and MUD-HCT, but the relapse rate was higher among SIB donor recipients when compared to MUD (38.5 versus 7%, P=0.02). RIC with fludarabine plus melphalan was associated with durable disease control and acceptable toxicity in this high-risk cohort.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/uso terapêutico , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Adulto , Idoso , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Melfalan/toxicidade , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/prevenção & controle , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Vidarabina/uso terapêutico , Vidarabina/toxicidadeRESUMO
Hyperthermic antiblastic isolated hepatic perfusion (IHP) with melphalan has been recently proposed as an alternative therapeutic option for patients with unresectable liver tumors. Although melphalan-heat antiblastic synergism is at a maximum at temperatures higher than 41 degrees C, IHP has so far been performed in humans at lower temperatures. In this experimental work, we compared IHP under mild versus true hyperthermic conditions in terms of drug pharmacokinetics and liver function. Ten pigs were submitted to IHP with melphalan 1.5 mg/kg at a mean temperature of 40 degrees C (group A, n = 5) or 42 degrees C (group B, n = 5). After a 60-minute perfusion, a 15-minute washout was performed. Perfusate-to-plasma leakage was monitored using scintigraphy. Throughout perfusion, samples from the systemic blood, perfusate, and liver parenchyma were obtained to measure melphalan concentrations. Liver function was assessed using standard blood tests and the indocyanine green-based test. No deaths related to the IHP procedure were recorded. All animals had transient liver function impairment, with all liver function test results returning to normal within the observation period. At histologic examination, liver damage was similar under both hyperthermic conditions. Melphalan levels in the perfusate were not significantly different in the two study groups (the mean perfusate/plasma area under the curve from 0 to 60 minutes ratios were 463 and 501, respectively). These results correlated well with those obtained using the scintigraphic method. Liver drug concentrations remained unchanged after true hyperthermia IHP. Under true hyperthermic conditions, neither an increase in liver parenchyma toxicity nor changes in melphalan pharmacokinetics were observed. These findings support the use of true hyperthermia in the clinical setting to exploit fully the antitumor synergism between melphalan and heat.
Assuntos
Antineoplásicos Alquilantes/farmacocinética , Quimioterapia do Câncer por Perfusão Regional/métodos , Hipertermia Induzida/métodos , Testes de Função Hepática , Fígado/efeitos dos fármacos , Melfalan/farmacocinética , Animais , Antineoplásicos Alquilantes/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Estudos de Viabilidade , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Fígado/diagnóstico por imagem , Fígado/patologia , Melfalan/toxicidade , Cintilografia , Suínos , Agregado de Albumina Marcado com Tecnécio Tc 99m/farmacocinética , TemperaturaRESUMO
It has been established that hyperthermia can enhance cytotoxicity of some chemotherapeutic agents. This has led to various clinical trials of thermochemotherapy, although many questions remain unanswered. The effects of various agents have been studied on animal tumours with different histopathology at elevated temperatures. These studies indicated that alkylating agents were most effective to all tumours at a moderately elevated temperature. Cisplatin was also effective to all tumours, but its effectiveness at 41.5 degrees C was less than that of alkylating agents. To quantitatively study these findings, the magnitude of thermal enhancement of melphalan, an alkylating agent, and that of oxaliplatin, a new platinum compound, were studied at 37-44.5 degrees C by the colony formation assay. The dose of each agent was kept constant, and cell survival was determined as a function of treatment time. The cell survival curve was exponentially related with treatment time at all test temperatures, and the T(0) (the time to reduce survival from 1 to 0.37) decreased with an increasing temperature. These results suggested that the cytotoxic effect of these agents occurred with a constant rate at 37 degrees C, and the rate was facilitated with an increasing temperature. This suggests that heat can accelerate the cytotoxic chemical reaction, leading to substantial thermal enhancement. The thermal enhancement ratio (TER, the ratio of the T(0) at 37 degrees C to the T(0) at an elevated temperature) increased with an increase in the temperature. The activation energy for melphalan at moderately elevated temperatures was largest among the agents tested in the laboratory and that for oxaliplatin was approximately half of the melphalan activation energy. This suggests that the thermal enhancement for the cytotoxicity of melphalan or alkylating agents might be the greatest. Potential mechanisms of thermal enhancement of cytotoxicity were discussed.
Assuntos
Antineoplásicos Alquilantes/toxicidade , Antineoplásicos/toxicidade , Hipertermia Induzida , Melfalan/toxicidade , Compostos Organoplatínicos/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Técnicas In Vitro , Oxaliplatina , Temperatura , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
In 90 consecutive patients with multiple myeloma, we investigated the feasibility of administering a tandem high-dose therapy regimen, using whole blood for rescue after the first and leucapheresis harvested between the two high doses, for rescue after the second high dose. After 5 days of G-CSF 1 litre of whole blood (WB) was obtained, left undisturbed at 4 degrees C and reinfused 24 h after HDM (140 mg/m(2)). Patients not in progression after 3-6 months were again mobilised, leucapheresed and treated with busulphan 16 mg/kg and cyclophosphamide 120 mg/kg (Bu/Cy) and reinfusion. In 90 patients, WB contained a mean (range) of 0.57 (0.02-3.22) x 10(6)/kg CD34(+) cells. Recovery after HDM was in 13 days for granulocytes and in 18 days for platelets, with 11 patients not recovering within 3 months. There were three toxic deaths. Sixty-six patients qualified for harvesting after HDM. In the first 11, marrow was harvested. The subsequent 55 patients were mobilised and in 45 the preset minimum of 1.5 x 10(6) CD34(+) cells was obtained. Forty-nine patients actually received Bu/Cy. Recovery after Bu/Cy and marrow reinfusion was in 35 days for granulocytes and 20 days for platelets, with two of five patients not recovering after 3 months. After Bu/Cy and leucapheresis reinfusion, recovery was in 17 days for granulocytes and in 34 days for platelets. Nine patients did not recover within 3 months. There were four toxic deaths. The median overall survival from diagnosis for patients receiving HDM was 49 months and for patients also receiving Bu/Cy, 84 months. We conclude that WB rescue after HDM followed by leucapheresis and a second transplant is feasible in the majority of patients. Better mobilisation techniques are required to increase the number of patients who can receive the second transplant.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transfusão de Sangue Autóloga/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucaférese/métodos , Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Adulto , Antineoplásicos Alquilantes/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Bussulfano/administração & dosagem , Bussulfano/toxicidade , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Ciclofosfamida/toxicidade , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Masculino , Melfalan/toxicidade , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Transplante Autólogo/métodos , Transplante Autólogo/mortalidade , Transplante Autólogo/normas , Resultado do TratamentoAssuntos
Amiloidose/terapia , Transfusão de Sangue Autóloga , Cardiomiopatias/terapia , Transplante de Células-Tronco Hematopoéticas , Amiloidose/complicações , Antígenos CD34/análise , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/toxicidade , Cardiomiopatias/complicações , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/toxicidade , Pessoa de Meia-Idade , Choque Cardiogênico/induzido quimicamente , Células-Tronco/imunologiaRESUMO
The role of more intense conditioning for second transplant was evaluated in myeloma patients achieving at least partial remission (PR) after first transplant with melphalan at 200 mg/m2. Forty-three patients received more intensive conditioning for the second transplant. Nineteen patients received cyclophosphamide 120 mg/kg along with melphalan 200 g/m2 (MEL-CY; group 1) while 24 patients received total body irradiation (1125 cGy) in conjunction with melphalan 140 mg/m2 (MEL-TBI; group 2). Forty-three matched control patients were identified from 450 patients receiving melphalan alone for second transplant (MEL200; group 3). Engraftment and toxicities were comparable among the groups with the exception of increased treatment-related mortality of 8% in group 2 compared to none in groups 1 and 3 (P = 0.07). Despite identical CR rates of 74, 71 and 70%, respectively, in groups 1, 2 and 3 (P = 1.0), event-free survival (median: 27, 15 and 61; P < 0.0001) and overall survival (median: 39, 25 and 76 months; P = 0.003) were significantly decreased in patients receiving more intensive conditioning (groups 1 and 2). Lymphocyte recovery, evaluated as a surrogate for immune recovery, was inferior in more intensively treated patients (groups 1 and 2 compared to group 3). Our findings suggest that more intense conditioning appears to have no benefit in patients responding to their first cycle of high-dose therapy and may even be detrimental in this setting. Bone Marrow Transplantation (2000) 25, 483-487.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Ciclofosfamida/administração & dosagem , Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Condicionamento Pré-Transplante , Transplante Autólogo/efeitos adversos , Irradiação Corporal Total , Antígenos CD34/metabolismo , Antineoplásicos Alquilantes/toxicidade , Estudos de Coortes , Terapia Combinada , Ciclofosfamida/toxicidade , Intervalo Livre de Doença , Estudos de Avaliação como Assunto , Febre/induzido quimicamente , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Contagem de Linfócitos , Melfalan/toxicidade , Pneumonia/induzido quimicamente , Prognóstico , Sepse/induzido quimicamente , Estomatite/induzido quimicamente , Taxa de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Microglobulina beta-2/sangueRESUMO
We studied the effects of aqueous knotweed extracts in alkeran-induced experimental pathozoospermia. Therapeutic effect of knotweed extract in experimental cytostatic hypogonadism was demonstrated (the preparation improved spermatozoon motility).
Assuntos
Antineoplásicos Alquilantes/toxicidade , Melfalan/toxicidade , Plantas Medicinais , Polygonaceae , Espermatozoides/efeitos dos fármacos , Animais , Masculino , Oligospermia/induzido quimicamente , Oligospermia/tratamento farmacológico , Extratos Vegetais/farmacologia , Ratos , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/patologiaRESUMO
Tumour-selective acidification is of potential interest for enhanced therapeutic gain of pH sensitive drugs. In this study, we investigated the feasibility of a tumour-selective reduction of the extracellular and intracellular pH and their effect on the tumour response of selected anti-cancer drugs. In an in vitro L1210 leukaemic cell model, we confirmed enhanced cytotoxicity of chlorambucil at low extracellular pH conditions. In contrast, the alkylating drugs melphalan and cisplatin, and bioreductive agents mitomycin C and its derivative EO9, required low intracellular pH conditions for enhanced activation. Furthermore, a strong and pH-independent synergism was observed between the pH-equilibrating drug nigericin and melphalan, of which the mechanism is unclear. In radiation-induced fibrosarcoma (RIF-1) tumour-bearing mice, the extracellular pH was reduced by the mitochondrial inhibitor m-iodobenzylguanidine (MIBG) or its analogue benzylguanidine (BG) plus glucose. To simultaneously reduce the intracellular pH, MIBG plus glucose were combined with the ionophore nigericin or the Na+/H+ exchanger inhibitor amiloride and the Na+-dependent HCO3-/Cl- exchanger inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS). Biochemical studies confirmed an effective reduction of the extracellular pH to approximately 6.2, and anti-tumour responses to the interventions indicated a simultaneous reduction of the intracellular pH below 6.6 for at least 3 h. Combined reduction of extra- and intracellular tumour pH with melphalan increased the tumour regrowth time to 200% of the pretreatment volume from 5.7 +/- 0.6 days for melphalan alone to 8.1 +/- 0.7 days with pH manipulation (P < 0.05). Mitomycin C related tumour growth delay was enhanced by the combined interventions from 3.8 +/- 0.5 to 5.2 +/- 0.5 days (P < 0.05), but only in tumours of relatively large sizes. The interventions were non-toxic alone or in combination with the anti-cancer drugs and did not affect melphalan biodistribution. In conclusion, we have developed non-toxic interventions for sustained and selective reduction of extra- and intracellular tumour pH which potentiated the tumour responses to selected anti-cancer drugs.
Assuntos
3-Iodobenzilguanidina/toxicidade , 3-Iodobenzilguanidina/uso terapêutico , Antineoplásicos/toxicidade , Antineoplásicos/uso terapêutico , Guanidinas/toxicidade , Concentração de Íons de Hidrogênio , Leucemia L1210/tratamento farmacológico , Ácido 4,4'-Di-Isotiocianoestilbeno-2,2'-Dissulfônico/farmacologia , Amilorida/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clorambucila/toxicidade , Radioisótopos de Cromo , Doxorrubicina/toxicidade , Sinergismo Farmacológico , Ácido Edético/farmacocinética , Glucose/farmacologia , Rim/efeitos dos fármacos , Rim/fisiologia , Melfalan/toxicidade , Camundongos , Mitomicina/toxicidade , Células Tumorais CultivadasRESUMO
Experience with limb perfusion-hyperthermia, TNF, and L-PAM suggests dramatic clinical responses in sarcoma and malignant melanoma. To extrapolate these results to clinical 41.8 degrees C whole-body hyperthermia (WBH) and systemic therapy, we studied the cytotoxic interactions of TNF, L-PAM and hyperthermia in L929 cells. The optimal sequence was TNF preceding 41.8 degrees C hyperthermia by 48 h, and L-PAM given simultaneously with heat. Trimodality synergism between TNF, hyperthermia and L-PAM was demonstrated. Non-cytotoxic doses of TNF had a super-additive interaction with L-PAM/heat. Conversely, non-cytotoxic doses of L-PAM had super-additive interactions with TNF followed by hyperthermia. Relative to therapeutic index, we studied WBH, L-PAM and TNF in non-tumor bearing mice. The optimal trimodality sequence did not result in increased normal tissue toxicity compared to L-PAM alone. The concentrations and sequencing of TNF and L-PAM studied are consistent with clinical application to WBH.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Hipertermia Induzida , Animais , Terapia Combinada , Interações Medicamentosas , Feminino , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/terapia , Melfalan/administração & dosagem , Melfalan/toxicidade , Camundongos , Camundongos Endogâmicos AKR , Células Tumorais Cultivadas/efeitos dos fármacos , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/toxicidadeRESUMO
Hyperthermia was combined with bleomycin, melphalan and cis-platinum in order to examine cell lethality and oncogenic transformation in C3H10T1/2 cells from the adjuvant use of heat with chemotherapy agents. When cells were exposed concurrently to 42.5 degrees C and each of the three chemotherapy agents, heat enhanced both the cytotoxic and oncogenic potential of the drugs. Hyperthermia-enhanced ratios were largest for bleomycin-treated cells. Examination of transformation incidences expressed as a function of surviving fraction, i.e. the cytotoxicity of treatment and therefore drug-heat efficacy, showed that for a given level of cell killing the combination of heat and cis-platinum resulted in fewer transformants per surviving cell than for cis-platinum alone. Hyperthermia appears to reduce the oncogenic potential of low concentrations of melphalan but has no effect on bleomycin-induced oncogenic transformation.
Assuntos
Antineoplásicos/toxicidade , Transformação Celular Neoplásica/efeitos dos fármacos , Temperatura Alta , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Bleomicina/toxicidade , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/toxicidade , Terapia Combinada , Humanos , Hipertermia Induzida , Melfalan/toxicidade , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/terapiaRESUMO
Both hyperthermia and glutathione depletion have been shown to increase the antineoplastic activity of melphalan. Investigations were carried out to define the toxicity and activity of melphalan given in conjunction with local (right hind limb) hyperthermia and L-buthionine-SR-sulphoximine (BSO)-mediated glutathione depletion to athymic mice bearing the melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR. Administration of 0.5 of the 10% lethal dose of melphalan to mice treated with BSO and hyperthermia (42 degrees C for 70 min) resulted in a 53% mortality rate. The mortality rates for mice treated with melphalan alone (2.5%), hyperthermia alone (0%), melphalan plus BSO (13.5%), melphalan plus hyperthermia (12.0%) and BSO plus hyperthermia (0%) were substantially lower than triple therapy. Histological examination of kidney, liver, colon, and small intestine sections taken from non-tumour-bearing animals revealed a marked increase in damage to the small intestine (cryptal necrosis and epithelial denudement) in animals receiving triple therapy compared with animals receiving any other treatment combination. Gavage administration of sterile water (1 ml twice a day) completely prevented mortality in animals receiving triple therapy. Treatment of tumour-bearing animals with triple therapy plus gavage demonstrated a statistically significant increase in tumour growth delay compared with animals receiving any other treatment combination.
Assuntos
Sistema Digestório/efeitos dos fármacos , Hipertermia Induzida/efeitos adversos , Melfalan/toxicidade , Animais , Antimetabólitos Antineoplásicos/toxicidade , Butionina Sulfoximina , Terapia Combinada , Sistema Digestório/patologia , Feminino , Glutationa/metabolismo , Humanos , Masculino , Metionina Sulfoximina/análogos & derivados , Metionina Sulfoximina/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/terapiaRESUMO
The maximum tolerated dose of melphalan combined with whole body hyperthermia (WBH) in dogs with spontaneous malignant melanoma was lower than in dogs not receiving WBH by a factor of 1.9 +/- 0.71. Thirty-three dogs were treated monthly with escalating doses of melphalan and followed weekly for toxicity and, when possible, tumour response. Toxicity was manifested as myelosuppression with nadir neutrophil and platelet counts occurring at 7-10 days post-treatment. The TD50 (+/- S.E.), defined by logistic regression analysis, was 0.63 (+/- 0.07) mg/kg and 0.33 (+/- 0.10) mg/kg for melphalan alone and combined with WBH, respectively. Objective tumour response in this limited series occurred in three of fourteen evaluable dogs (three of eleven treated with melphalan alone and none of three treated with WBH plus melphalan). It is concluded that melphalan combined with WBH can be safely administered, although a reduction in dose is necessary. A randomized clinical trial is required to investigate the possibility of achieving therapeutic benefit from combined melphalan and WBH.
Assuntos
Doenças do Cão/terapia , Hipertermia Induzida , Melanoma/veterinária , Melfalan/uso terapêutico , Animais , Terapia Combinada , Doenças do Cão/tratamento farmacológico , Cães , Tolerância a Medicamentos , Estudos de Avaliação como Assunto , Melanoma/tratamento farmacológico , Melanoma/terapia , Melfalan/administração & dosagem , Melfalan/toxicidadeRESUMO
This study primarily describes the cytostatic activity of a bisphosphonate and of an alkylating agent linked bisphosphonate toward mammary carcinomas in vivo. Bisphosphonates had been shown to be therapeutically active in bone metastases. There is no animal tumor model available in which both primary mammary carcinomas and bone metastases can be studied simultaneously. Therefore, the Walker carcinosarcoma model, which was used as a model for bone metastasis in earlier studies, was combined with the M-methyl-N-nitrosourea (MNU) induced mammary carcinoma as a model for the primary tumor. Four-, or six-week treatment of MNU-induced mammary carcinomas in Sprague-Dawley rats with the new aromatic bisphosphonate 4[4-[bis(2-chloroethyl)-amino]-phenyl]-1-hydroxybutane-1, 1-bisphosphonate (BAD) showed higher antitumor activity than treatment with melphalan or with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD) alone. BAD is the APD moiety covalently bound to a molecule derived from melphalan. A combination therapy with 11.75 mg/kg/day APD and 0.6 mg/kg/day melphalan showed the best therapeutic efficacy in this tumor model. In comparison to monotherapy with BAD, APD, or melphalan, a significantly higher rate of complete remissions was achieved. APD, itself, was not genotoxic in 3 employed short term assays. Since bisphosphonates had been shown to be therapeutically active in bone metastases, the antitumor potency of these compounds against experimental primary mammary carcinomas, coupled with the non-genotoxicity of APD and the inhibition of osteolytic bone metastases, might be an important advancement for adjuvant chemotherapy of human mammary carcinomas.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Difosfonatos/administração & dosagem , Difosfonatos/toxicidade , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Melfalan/administração & dosagem , Melfalan/toxicidade , Metilnitrosoureia , Testes de Mutagenicidade , Compostos de Mostarda Nitrogenada/administração & dosagem , Compostos de Mostarda Nitrogenada/toxicidade , Pamidronato , Ratos , Ratos Endogâmicos , Salmonella typhimurium/genéticaRESUMO
We have previously reported that chloroethyl nitrosourea and nitrogen mustard bone marrow toxicity can be selectively reduced by placement of the cytotoxic group on specific positions of a glucose molecule. We have now synthesized and evaluated a new drug in which the mustard cytotoxic group is attached to the carbon-6 position of galactose (C6-GLM). C6-GLM, administered i.p. as a single 10% lethal dose of 15.5 mg/kg, produced a 121% increase in life span (ILS) in mice bearing the ascitic P388 leukemia, compared to a 60% ILS with a 10% lethal dose of nitrogen mustard (P less than 0.01). A single p.o. dose of C6-GLM, 16 mg/kg, produced an ILS of 58%. Against i.p.-implanted B-16 melanoma, i.p. C6-GLM produced a 56% ILS compared to 30% with an equitoxic dose of nitrogen mustard (P less than 0.01). The activity of the two drugs for Ehrlich ascites was comparable, with 60% survivors with the galactose mustard. A single 10% lethal dose of C6-GLM reduced the white blood cells to 74% of control; circulating granulocytes remained at 91% of initial values. With nitrogen mustard, the nadir white blood cell count was 57% of control with an absolute granulocyte count of 70% of initial values (P less than 0.01). The toxicity of melphalan was considerably greater, with a lower and more protracted while blood cell nadir and an absolute neutrophil count nadir of 49% of control. These findings paralleled the relative decrements in bone marrow DNA synthesis produced by the three drugs. Measurement of human bone marrow granulocyte-macrophage colony-forming units, following in vitro exposure to graded concentrations of the three mustards, confirmed the bone marrow sparing properties of C6-GLM. At the highest concentration, 1 X 10(-2) mM, the latter drug produced only a 33% reduction in colonies compared to a 75% reduction with nitrogen mustard and a virtual elimination of activity of colony-forming units with melphalan. The demonstration of antitumor activity, at least equivalent to nitrogen mustard, without the necessity of significant bone marrow toxicity supports the development of C6-GLM for clinical trials in humans.
Assuntos
Medula Óssea/patologia , Galactosamina/análogos & derivados , Células-Tronco Hematopoéticas/citologia , Leucemia P388/tratamento farmacológico , Leucemia Experimental/tratamento farmacológico , Animais , Medula Óssea/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Galactosamina/uso terapêutico , Galactosamina/toxicidade , Células-Tronco Hematopoéticas/efeitos dos fármacos , Leucopenia/induzido quimicamente , Masculino , Mecloretamina/toxicidade , Melfalan/toxicidade , Camundongos , Camundongos Endogâmicos DBA , Neutrófilos/citologia , Relação Estrutura-AtividadeRESUMO
Cisplatin and L-PAM are DNA-crosslinking anticancer agents which have not been systematically studied for vesicant potential. Mitoxantrone is a new active anthracene-based, DNA intercalator which is undergoing widespread clinical testing for antitumor efficacy in man. These three agents were tested for vesicant activity in dehaired BALB/c mice given ID injections equivalent to human clinical doses. Neither cisplatin (up to 150 mg/m2) nor L-PAM (up to 71 mg/m2) produced any skin necrosis in the mice. The L-PAM solvent (acid/alcohol in propylene glycol) was ulcerogenic if injected undiluted. Mitoxantrone (up to 14 mg/m2) was not ulcerogenic in the mice, although the skin site retained a blue drug discoloration for several weeks. It is concluded that in clinically relevant doses, cisplatin, L-PAM, and mitoxantrone are not vesicants.
Assuntos
Antraquinonas/toxicidade , Cisplatino/toxicidade , Irritantes , Melfalan/toxicidade , Úlcera Cutânea/induzido quimicamente , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Injeções Intradérmicas , Camundongos , Camundongos Endogâmicos BALB C , MitoxantronaRESUMO
The enhancement of melphalan toxicity was observed by preincubation of V-79- 379A cells in spinner culture with multiple doses of misonidazole (miso) or SR-2508 under hypoxic conditions. Chemosensitization was shown to be a function of sensitizer concentration and duration of exposure to the alkylating agent. A preincubation exposure of cells with 5 mM miso reduced endogenous cell thiols to less than 5% of controls and enhanced melphalan toxicity by a factor of 4.7. Cells preincubated with miso not only had lower levels of nonprotein thiols, but also were shown to have altered levels of intracellular calcium and a lower threshold to oxidative stress as measured by toxicity to cysteamine or H2O2. Preincubated cells, hypoxic cells, and cells receiving moderate hyperthermia (42.5 degrees C for 3 hr) all showed increased sensitivity to either cysteamine or H2O2. The increased killing of preincubated cells by cysteamine was shown to be similar to that of H2O2, and the dramatic reduction of cysteamine toxicity by catalase indicated H2O2 was the major reaction associated with this effect. These results indicate that preincubated cells exhibit a variety of biological effects that may significantly influence their response to further treatment with drugs or radiation, especially where peroxidative and free radical mechanisms are involved. The depletion of endogenous thiols, calcium disturbance, and vulnerability to oxidative stress are factors to be considered when interpreting mechanisms of combined drug action and effects that may potentially be exploited in terms of therapeutic gains.
Assuntos
Hipóxia/fisiopatologia , Radiossensibilizantes/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cricetinae , Cisteamina/toxicidade , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Etanidazol , Peróxido de Hidrogênio/toxicidade , Hipertermia Induzida , Melfalan/toxicidade , Nitroimidazóis/toxicidade , Tolerância a Radiação , Fatores de TempoRESUMO
A mutant of Chinese hamster ovary cells, CHY-2, was isolated on the basis of its reduced ability to grow on a limiting concentration of leucine and was found to be defective in uptake of leucine via the sodium-independent L system. Consistent with published reports that the L system can mediate melphalan uptake, the D10 of the mutant for melphalan was increased threefold under conditions designed to limit drug uptake to the L system (brief exposure in sodium-free medium). Unlike a previously described melphalan-resistant CHO mutant (CHr), CHY-2 displays no cross-resistance to colchicine or puromycin. It differs from a second melphalan-resistant CHO mutant, melr, in its sensitivity to melphalan in the presence of high Na+, and from a melphalan-resistant mouse leukemic cell in possessing normal levels of intracellular glutathione. Thus, CHY-2 represents a new melphalan-resistant mutant class. The effect of the CHY-2 mutation is pleiotropic, involving significant reductions in amino acid uptake via the L, A and Ly+ (but not ASC) systems. The primary defect is unknown; however, the mutant possesses normal intracellular concentrations of Na+ and K+ and normal membrane fluidity. The growth rate of the mutant in standard medium is greatly reduced (generation time of 60 h vs. 24 h), although it can be improved by the addition of a supplement containing high concentrations of leucine, proline, and peptides.