RESUMO
PURPOSE: The purpose of this phase I study was to evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), the recommended dose for phase II study, pharmacokinetics, and antitumor activity of TZT-1,027 (soblidotin) in patients with non-small cell lung cancer (NSCLC) when administered every 3-4 weeks. METHODS: Eligible patients had the following characteristics: stage III/b or IV NSCLC that was refractory to conventional therapy or for which no standard therapy was available; Eastern Cooperative Oncology Group (ECOG) performance status (PS)
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Carcinoma Pulmonar de Células não Pequenas/patologia , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Doenças Hematológicas/sangue , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/epidemiologia , Humanos , Injeções Intravenosas , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Oligopeptídeos/farmacocinética , Resultado do TratamentoRESUMO
Prostate cancer incurs a substantial incidence and mortality burden, similarly to breast cancer, and it ranks among the top ten specific causes of death in the United States. It is inherent as we maximize the detection of early prostate cancer that we increase the detection of both nonaggressive (slow growing) and aggressive (faster growing) prostate cancers. The evidence clearly supports the use of PSA screening in conjunction with DRE as a means of early detection of prostate cancer. Widespread implementation of prostate cancer screening in the United States has led to the phenomenon of stage migration with more cancers being detected at a lower stage. Such a trend has decreased the incidence of metastatic disease at diagnosis and paralleled the decrease of the mortality rate from prostate cancer. Our understanding of the natural history of prostate cancer is progressing over time, but the question of its length is unanswerable. The relatively long doubling time (on average) of early prostate cancer of 3 to 4 years or more indicates a relatively good prognosis for many men with this disease, even without early detection and treatment. Unfortunately, the poor specificity of the PSA test in men with benign prostatic hyperplasia (BPH) leads to high rates of prostate biopsy and attendant illnesses and costs. Early detection is more apt to detect a slow-growing prostate cancer than a faster growing cancer that is associated with a more rapid course of progression to metastatic disease. Hence, the launching of mass screening programs for the early detection of prostate cancer is premature. However, in the absence of solid evidence of benefit, one reasonable approach to screening at the individual level is to involve the patient in decisions about whether or not to perform a PSA test. Thus, "offering" PSA testing must be accompanied by informed discussion within the context of an ongoing patient-physician relationship. This is to be distinguished from the use of PSA testing for the purpose of "mass screening." Concepts that must be explored with the patient include: 1. The long-term ramifications of screening 2. The relatively high probability of further evaluation and biopsy with positive results 3. Potentially difficult decisions that may arise about using treatments that are associated with considerable morbidity and uncertain benefits (at the time) if cancer is discovered We should identify a future path that is evidence-based, focused on the issues that make a difference to patients, and results in better and longer lives of those with the disease and those who are at risk of getting it. If that path leads to treating fewer patients in the future, even if sometimes more aggressively, we should pursue it definitely and consequently.
Assuntos
Programas de Rastreamento , Neoplasias da Próstata/diagnóstico , Humanos , Masculino , Prognóstico , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/terapiaRESUMO
The lineage-specific human tyrosinase promoter has been used to successfully target gene expression at the transcriptional level to melanoma cells. The tyrosinase promoter, alone and in combination with a single, or a dual, tandem melanocyte-specific enhancer, was used to regulate expression of the firefly luciferase reporter gene. Transient transfections of these tissue-specific luciferase constructs in human and murine melanoma (Pmel, B16mel) and colon carcinoma (WiDr, MC38) cell lines resulted in melanoma-specific luciferase expression that was amplified 5- and 500-fold with the addition of a single or double enhancer, respectively, to the tyrosinase promoter. When the double enhancer-promoter construct expressed the highly toxic Escherichia coli purine nucleoside phosphorylase (PNP) gene, transfection of the same cell lines followed by administration of the prodrug 6-methyl purine deoxyriboside (6-MPDR) at a concentration of 50 microM caused melanoma-specific in vitro cell killing. Within 5 days after prodrug administration methylthiazol-tetrazolium (MTT) cytotoxicity assays showed that only 15 and 9% of Pmel and B16mel cells, respectively, remained viable compared with controls. This effect was highly specific, as 90 and 96% of WiDr and MC38 colon carcinoma cells remained viable 5 days after identical treatment. This effect was a direct result of increased tissue-specific conversion of 6-MPDR to the toxic metabolite 6-methylpurine (6-MP), as documented by HPLC analysis of culture supernatants. These results show that the dual tandem melanocyte-specific enhancer provides powerful amplification of the transcriptional targeting of gene expression afforded by use of the tyrosinase promoter. This amplification translates into increased, highly specific cytotoxicity to melanoma by the PNP/6-MPDR enzyme/prodrug system and, therefore, has potential efficacy in the use of gene therapy for the treatment of metastatic melanoma.
Assuntos
Elementos Facilitadores Genéticos , Regulação Neoplásica da Expressão Gênica , Melanoma Experimental/genética , Purina-Núcleosídeo Fosforilase/genética , Animais , Sequência de Bases , Sobrevivência Celular/genética , Citomegalovirus/genética , Primers do DNA , Humanos , Melanócitos/metabolismo , Melanoma Experimental/patologia , Camundongos , Monofenol Mono-Oxigenase/genética , Regiões Promotoras Genéticas , Nucleosídeos de Purina/metabolismo , Regulação para CimaRESUMO
Prolactin is an important physiological regulator of prostate development and growth in preclinical models. In prostate cancer there is strong evidence that prolactin exerts a trophic effect independent of testosterone. In addition, patients with prostate cancer that have an elevated prolactin level correlated with a poorer prognosis. Based on these data, we evaluated the clinical effect of prolactin suppression using bromocriptine in patients with androgen-independent prostate cancer. We conducted an open-label phase II trial of bromocriptine in patients with progressive metastatic prostate cancer. Basal and thyrotropin releasing hormone (TRH)-stimulated prolactin levels were utilized as biological endpoints for determining the dose of bromocriptine. All patients continued to receive complete androgen blockade. Thirteen patients were enrolled (median age 69.5 years). There were no complete or partial responses associated with bromocriptine in 11 of the evaluable patients. The mean duration of bromocriptine treatment was 8.2 weeks (2-14 weeks). One patient had a clinically insignificant decrease in prostate-specific antigen (PSA) and another patient had a 19.9% decrease in PSA with progression of a soft tissue mass. The vast majority of patients (10 of 11) had suppression of prolactin with a bromocriptine dose of 2.5 mg three times a day. One patient required a dose adjustment due to inadequate suppression, with a final maintenance dose of bromocriptine 12.5 mg per day resulting in complete suppression. No serious treatment-related toxicities were observed. The most common complications noted were nausea, headaches, dizziness, and fatigue. Our data showed that 2.5 mg three times per day of bromocriptine suppressed prolactin in 90% of the patients. Furthermore, this dose appears to be well tolerated.
Assuntos
Adenocarcinoma/tratamento farmacológico , Androgênios/fisiologia , Antineoplásicos/uso terapêutico , Bromocriptina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Antineoplásicos/efeitos adversos , Bromocriptina/efeitos adversos , Seguimentos , Humanos , Masculino , Neoplasias da Próstata/fisiopatologia , Resultado do TratamentoRESUMO
Interviews were conducted with 63 women aged 18-75 shortly after their admission to hospital for routine non-cancer gynaecological surgery. Three groups were studied: major surgery, chiefly hysterectomy, carried out for benign conditions (n = 25); minor surgery such as dilatation and curettage (n = 29); fertility investigations and sterilisations (n = 9). Women were asked whether they worried if they were suffering from seven serious illnesses including heart disease, breast cancer and gynaecological cancer (cancer of the cervix, womb or ovaries). Significantly more women were concerned that they suffered from gynaecological cancer than any other illness. When asked why they were worried, over 85% of those expressing concern believed that their current gynaecological problem stemmed from cancer. Worry about gynaecological cancer was positively associated with psychiatric status and gynaecological knowledge, and negatively with satisfaction with treatment. A link with presenting clinical symptoms was also identified. This study revealed high levels of unwarranted distress in women undergoing routine surgery. Such fears may not be allayed, since surgeons and staff may not consider cancer to be relevant to the patient's clinical condition.
Assuntos
Ansiedade/psicologia , Neoplasias dos Genitais Femininos/psicologia , Procedimentos Cirúrgicos Operatórios/psicologia , Adolescente , Adulto , Idoso , Comunicação , Comportamento do Consumidor , Feminino , Neoplasias dos Genitais Femininos/cirurgia , Humanos , Pessoa de Meia-IdadeRESUMO
Following hormonal therapy, few treatment regimens have activity in metastatic prostate cancer. Cytotoxic agents have minimal activity in this disease. However, combinations of cytotoxic agents may be beneficial. The activity of estramustine, vinblastine, etoposide, and suramin on cell growth was evaluated. Prostate specific antigen (PSA) is routinely used as a surrogate marker for disease progression. Many pharmacological agents alter PSA levels independently of their effect on tumor growth, the effect of these agents on PSA secretion was determined. Each agent was evaluated alone and in combination with the other drugs in two prostate cancer cell lines. In LNCaP cells, estramustine and suramin were cytostatic, while vinblastine and etoposide were cytotoxic. Estramustine down-regulated etoposide PSA secretion, while suramin had no effect. The effects of etoposide and vinblastine on PSA secretion were not evaluable. In PC-3 cells, only etoposide was cytotoxic. Tandem combinations were more cytotoxic than single agents in both cell lines. The addition of a third agent to the tandem combination produced less cytotoxicity. In our hands, the best combinations were estramustine/vinblastine, suramin/vinblastine, and suramin/etoposide. These combinations yielded 20-60% higher cytotoxicity than any of the drugs alone.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Estramustina/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Masculino , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Suramina/administração & dosagem , Células Tumorais Cultivadas , Vimblastina/administração & dosagemRESUMO
Between December 1979 and July 1986, 190 patients with nonseminomatous germ-cell testicular tumors were treated according to the modified Einhorn scheme. The response rate was 67.89%. The most favorable results were found in the embryonal histologic type (RR = 76.9%), in the biological marker (AFP, HCG) negative (RR = 97.43%) and in the minimal pulmonary extent group (RR = 94.12%).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Testiculares/tratamento farmacológico , Adolescente , Adulto , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Vimblastina/efeitos adversos , Vimblastina/uso terapêuticoRESUMO
The authors describe the evidence and results obtained in 21 out of 100 patients who underwent salvage retroperitoneal lymphadenectomy for advanced testicular cancer (UICC stage II/B bulky and stage III) in the period 1982-1993, and in whom inductive chemotherapy was not followed by marker conversion. It is stated that if AFP positivity is low (titres below 100 ng/ml) salvage retroperitoneal lymphadenectomy (RLA) is of high therapeutic value, whereas in all cases with HCG positivity or AFP titres higher than 500 ng/ml tumorous death ensued without exception. In our cases viable tumour residues occurred in 81%. Salvage resection was feasible in 76%, but every incomplete resection (19%) was followed by death due to tumour. In all but one of the cases marker positivity, an indicator of therapy-resistant viable tumour residues, persisted after having used more than four PVB combinations or changes in the chemotherapeutic regimen.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Germinoma/terapia , Excisão de Linfonodo , Espaço Retroperitoneal/cirurgia , Terapia de Salvação , Neoplasias Testiculares/terapia , Terapia Combinada , Seguimentos , Germinoma/metabolismo , Germinoma/patologia , Humanos , Masculino , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologiaRESUMO
The authors compared the effectivity of doxycyclin or ofloxacin after combined chemotherapy of testicular cancer patients during the leukopenic periods. Between 1988 and 1991 200 patients were randomized and 194 were evaluated. One hundred and fifty two patients had been treated by cytostatic treatment earlier 2.5 or 2.9 times and 17 by irradiation. The average age was 30.1 in the doxycyclin group and 31.5 years in ofloxacin group. The patients characteristics in average age and previous treatments were not significant in the two groups. Doxycyclin was applied at the first day 200 mg and the following days 100 mg for 6.8 days and ofloxacin was given 2 times 100 mg day for 8.0 days. The preventive antibiotic treatment was insufficient in 16 or 6 cases requiring the the new antibiotic therapy. The development of the new infectional lesions was significantly higher in doxycyclin group and it needed the other antibiotic therapy. The condition of the patients did not require systemic antimycotic or antiviral therapy. The toxicity was lower in oflaxacin group. Tarivid is suitable for preventing the infection in neutropenic periods after the cytostatic therapy. The number of infections are decreased the completion with some penicillins. Regarding to previous cytostatic drugs the cephalosporins are suggested for prevention during the neutropenic periods.
Assuntos
Doxiciclina/uso terapêutico , Neutropenia/induzido quimicamente , Ofloxacino/uso terapêutico , Neoplasias Testiculares/tratamento farmacológico , Adulto , Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cefalosporinas/uso terapêutico , Relação Dose-Resposta a Droga , Doxiciclina/administração & dosagem , Humanos , Hungria , Masculino , Neutropenia/terapia , Ofloxacino/administração & dosagemRESUMO
One hundred ninety patients with germ cell line testicular tumours were treated according to the modified Einhorn scheme. The response rate was 67.9%. The most favourable results were found in the embryonal histologic type (RR = 76.9%) in the biological markers (beta-HCG and AFP) negative (RR = 97.4%) and in the minimal pulmonary extent group (RR = 94.1%). The authors treated 112 patients with including these VPB-resistant germ cell testicular tumour and those with recurrence after this treatment. The patients' mean age was 28.8 (limits 19 to 44) years. Patients were given Vepeside (100 mg/m in infusion for days 1-5), Adriablastin (40 mg/m in infusion on day 1) and Cisplatin (20 mg/m in infusion) for day 1-5. The treatment resulted in CR with 18 patients (16.1%) and PR with 42 (37.5%) (RR = 53.6%). The best results were obtained with the seminoma patients who were marker-negative and had small-volume metastasis. CR developed in 4 of 7 seminoma patients (57%) and in 7 of 25 marker-negative individuals (28%), and PR developed in 11 patients (44%) (RR = 72%). Out of 12 patients with small volume metastatis four (33%) showed CR and five revealed PR (41.7%), their RR turned out to be 74.6%. The average remission period was 37 (range 4-70) months in CR but merely 6.1 (range 2-38) months in PR. It can be stated that fairly good results can be achieved with second-line VpAP treatment in case of resistance developed to primary VPB therapy or subsequent relapse. The efficacy of combined chemotherapy of Vepesed+Holoxan +/- Adriablastin as third-choice was studied in advanced testicular cancer patients refractory to, or recurrent after, first- and second-line cytostatic therapy. Between September 1981 and January 1988 49 evaluable patients were treated with Vepesid (VP-16213--100 mg/m2 days 1-5), Holoxan (40 ml/kg days 1-5), hydration, urine-alkylation + Uromitexan +/- Adriablastin (40 mg/m day 1). The single dose of Uromitexan was 20% of the daily dose of Holoxan, and the patients received it i.v. just prior to Holoxan administration (h 0), the 4 and 8 h later. Two patients got into CR and 10 to PR. The rate of remission was 24.5%. The most severe side effect was leukopenia. The elevation of BUN and se. creatinine was transient and mild. In those cases where Holoxan was not included in the first- or second-line regimens, when combined with Vepesid and Adriablastin as third-choice therapy one could achieve further improvement. In case of CR the prolongation of life is also noteworthy. The first-, second- and third-line therapy plus salvage RLA and/or pulmonary metastasectomy achieved long-term survival only in one quarter of the patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Doxorrubicina/administração & dosagem , Resistência a Medicamentos , Etoposídeo/administração & dosagem , Humanos , Masculino , Metástase Neoplásica , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Testiculares/patologia , Falha de Tratamento , Vimblastina/administração & dosagemRESUMO
Prostate-specific antigen, PSA, is regarded as a reliable surrogate marker for androgen-independent prostate cancer (AIPC). Concern has been raised that investigational agents may affect PSA secretion without altering tumour growth or volume. In a phase I trial, several patients with AIPC had elevated serum PSA levels while receiving TNP-470 that reversed upon discontinuation. TNP-470 inhibits capillary growth in several angiogenesis models. These observations prompted us to determine if TNP-470, or its metabolite, AGM-1883, altered PSA secretion. Intracellular protein and transcriptional levels of PSA and androgen receptor were also determined. The highest TNP-470 concentration produced a 40.6% decrease in cell number; AGM-1883 had minimal effects on cell viability. PSA secretion per cell was induced 1.1- to 1.5-fold following TNP-470 exposure. The same trend was observed for AGM-1883. PSA and AR were transcriptionally up-regulated within 30 min after exposure to TNP-470. PSA transcription was increased 1.4-fold, while androgen receptor (AR) transcription was induced 1.2-fold. The increased PSA transcriptional activity accounts for the increased PSA secretion. Increased AR transcription was also reflected at the protein level. In conclusion, TNP-470 and AGM-1883 both up-regulated PSA making clinical utilization of this surrogate marker problematic.
Assuntos
Acetamidas/farmacologia , Antibióticos Antineoplásicos/farmacologia , Neovascularização Patológica/prevenção & controle , Antígeno Prostático Específico/efeitos dos fármacos , Receptores Androgênicos/efeitos dos fármacos , Sesquiterpenos/farmacologia , Compostos de Espiro/farmacologia , Contagem de Células/efeitos dos fármacos , Cicloexanos , Humanos , Masculino , O-(Cloroacetilcarbamoil)fumagilol , Antígeno Prostático Específico/metabolismo , Receptores Androgênicos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Transcrição Gênica/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismoRESUMO
INTRODUCTION: Due to in vitro data suggesting antitumor activity with gallium nitrate, we sought to evaluate the safety and activity in patients with androgen-independent prostate cancer. METHOD: Patients were eligible for this study if they had an ECOG performance status of < or = 2, stage D2 metastatic prostate cancer that was progressing following combined androgen ablation (medical or surgical castration plus antiandrogen) and had failed antiandrogen withdrawal. Therapy consisted of gallium nitrate (200 mg/m(2)/day) as a continuous infusion for 7 days, administered every 21 days, with hydration (100 ml/m(2)/h). Individuals that had previously received suramin were treated at a dose of 150 mg/m(2)/day of gallium nitrate. RESULTS: Eight patients were enrolled: 4 patients at the 200 mg/m(2)/day dose level and 4 patients at the lower dosage (150 mg/m(2)/day). One of 8 patients had a >75% decline in prostate-specific antigen (PSA), 3 patients had stable PSA values for 17, 18 and 22 weeks, and 4 patients had progression by PSA (>50% increase over baseline). Anemia requiring transfusion occurred in 5 of 8 patients (63%). Two patients (25%) developed grade 4 toxicity: 1 patient developed complete blindness with partial reversal over 12 months, and another patient had pulmonary infiltrates, hypoxemia, and fever. Serious adverse events were not correlated to prior suramin exposure, or gallium plasma concentrations (total or free), but appeared to be related to cumulative cycles of gallium nitrate. Remaining adverse events were grade 1 or 2. No patients developed renal or neurological toxicity. CONCLUSION: This trial was prematurely terminated because repeated administration of gallium nitrate was poorly tolerated in an elderly population with androgen-independent prostate cancer. Gallium had modest clinical activity in this disease.