RESUMEN
Hepsulfam (1,7-heptanediol disulfamate, NSC 329680) is a new antineoplastic alkanesulfonate agent which has demonstrated a broader preclinical activity than busulfan. The compound is currently undergoing clinical trials. We have studied the activity of hepsulfam and busulfan simultaneously in human tumor xenografts in vitro in a clonogenic assay and in vivo in tumor-bearing animals in order to assess the activity of both compounds in model systems of slowly growing malignancies. In a total of 37 different tumors of various histologies, both agents demonstrated broad spectrum in vitro activity. The median IC50 of hepsulfam and busulfan was determined as 0.93 and 3.31 micrograms/ml, respectively. At a concentration of 1.0 micrograms/ml, hepsulfam was active in eight of 37 tumors (22%) in the clonogenic assay, whereas busulfan effected inhibition of colony formation in one of 37 lines (3%). At the same concentration, however, hepsulfam demonstrated a clear in vitro toxicity to human bone marrow cells (CFU-GM) from healthy donors, whereas busulfan did not reveal a myelosuppressive effect. Evaluation of equitoxic concentrations in vitro revealed a higher activity of hepsulfam, especially in non-small cell lung cancer. In tumor-bearing nude mice, the approximate LD10 dose was determined as 150 mg/kg single bolus injection given i.p. on day 1 for both compounds. Hepsulfam demonstrated superior in vivo activity in a large cell lung cancer xenograft and a gastric carcinoma model. The preclinical activity of hepsulfam suggests a possible role of this compound in the treatment of solid human malignancies. However, the increased bone marrow toxicity of hepsulfam as compared with busulfan might be critical for further clinical application.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antineoplásicos/farmacología , Enfermedades de la Médula Ósea/inducido químicamente , Busulfano/farmacología , Ácidos Sulfónicos/farmacología , Animales , Antineoplásicos/toxicidad , Busulfano/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Inyecciones Intraperitoneales , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Ácidos Sulfónicos/toxicidad , Trasplante HeterólogoAsunto(s)
Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Animales , Antraciclinas , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Femenino , Humanos , Ratones , Ratones Desnudos , National Institutes of Health (U.S.) , Trasplante de Neoplasias , Picolinas/química , Picolinas/farmacología , Polienos/química , Polienos/farmacología , Pirazinas/química , Pirazinas/farmacología , Sirolimus , Ácidos Sulfónicos/química , Ácidos Sulfónicos/farmacología , Terpenos/química , Terpenos/farmacología , Ensayo de Tumor de Célula Madre , Estados UnidosRESUMEN
The feasibility, evaluation and predictive value of the colony-forming assay with human tumor xenografts for screening anticancer drugs have been studied. Using human tumors grown in serial passage in nude mice, adequate colony formation was observed in 215 of 251 (86%) different solid human tumors of various histologies. Based on in vitro growth characteristics, a quality-controlled assay protocol was developed. With the proposed criteria for standardized evaluation of individual experiments a substantial increase in assay reliability was achieved. The five clinically established agents, cisplatin, doxorubicin, etoposide, mitomycin-C and vindesine, were studied for anticancer activity in the clonogenic assay. Drugs were applied over a wide dose range by continuous exposure, yielding clear dose-response effects with coefficients of correlation between r = 0.946 and 0.995. Relevant dose levels predicting correctly for the clinical efficacy of the agents were determined by comparison of in vitro anticancer activity to in vitro toxicity on human bone marrow as follows: cisplatin 0.1 micrograms/ml, doxorubicin 0.01 micrograms/ml, etoposide 0.1 micrograms/ml, mitomycin-C 0.005 micrograms/ml, vindesine 0.01 micrograms/ml. At these concentrations, clinically sensitive tumor types showed inhibition of colony formation in 99 of 240 cases (41%), whereas 11% (19/176) of clinically resistant tumors were responsive. The relevant dose levels used equal between 0.3% and 4.0% of the achievable peak plasma concentrations in man. The predictive value of the clonogenic assay was determined by treatment of the same tumors in vitro and in vivo in tumor-bearing nude mice. In 174/220 comparisons (79%), in vitro data predicted correctly for the in vivo sensitivity of the xenografted malignancies.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antineoplásicos/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales/métodos , Neoplasias/tratamiento farmacológico , Ensayo de Tumor de Célula Madre , Animales , Médula Ósea/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Femenino , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Valor Predictivo de las Pruebas , Control de Calidad , Reproducibilidad de los Resultados , Trasplante HeterólogoRESUMEN
We have shown previously that the flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone) enhances the antiproliferative activity of cis-diamminedichloroplatinum(II) (cis-DDP) in vitro. In order to investigate whether this observation could be exploited in cancer treatment, we tested this drug combination in human tumor xenografts. The established human large-cell cancer of the lung (LXFL 529) was implanted s.c. into nude mice. Tumors were allowed to grow to a mean diameter of approximately 5 mm and the animals were subsequently treated intraperitoneally with quercetin, cis-DDP or a combination of both. Treatment was given 3 times at 3-day intervals. Twenty milligrams quercetin per kg body weight caused no inhibition in tumor growth compared to untreated controls; 3 mg cis-DDP per kg body weight with the same time schedule reduced tumor growth, compared to quercetin-treated and control animals. Concomitant treatment with 20 mg quercetin and 3 mg cis-DDP per kg body weight reduced tumor growth to a significantly greater degree than cis-DDP alone. Toxicity of this treatment was relatively low as determined by measurements of the body weight of the mice. A combination of 4 mg or 5 mg cis-DDP with 20 mg quercetin per kg body weight also reduced tumor growth compared to single cis-DDP treatment. The toxicity of treatment with these increased doses was high, as shown by the high lethality and the loss of body weight of surviving animals.
Asunto(s)
Carcinoma de Células Pequeñas/tratamiento farmacológico , Cisplatino/uso terapéutico , Flavonoides/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Quercetina/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Cisplatino/administración & dosificación , Esquema de Medicación , Sinergismo Farmacológico , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Quercetina/administración & dosificaciónRESUMEN
The potential of evaluating the preclinical response of solid tumours was studied in human tumour xenografts in the clonogenic assay. Tumour specimens surgically removed from cancer patients were implanted subcutaneously into thymus-aplastic nude mice. Chemosensitivity of the mouse-grown tumours was tested with a modification of the double-layer soft-agar clonogenic assay. Tumour cells were tested against thirteen established cytostatic drugs at two dosages by continuous exposure. 62 retrospective in vivo/in vitro correlations were done. The clonogenic assay predicted correctly for clinical response in 16/27 (59%) and for resistance in 32/35 (91%). These correlation rates were similar to reported data for fresh solid human tumour specimens. The results support the clinical relevance of the nude mouse/clonogenic assay model.
Asunto(s)
Neoplasias/tratamiento farmacológico , Ensayo de Tumor de Célula Madre , Adulto , Anciano , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Trasplante de Neoplasias , Trasplante HeterólogoRESUMEN
The in vivo effects of the oxazaphosphorine compound ifosfamide (IFO) on human tumour xenografts were assessed in thymus aplastic nude mice. The human origin of the tumours was confirmed by isoenzymatic and immunohistochemical methods. Tumour models were selected from a panel of 180 regularly growing, well-characterized xenografts. The maximum tolerated dose in tumour-bearing nude mice was determined to be 130 mg/kg per day given on days 1-3 and 15-17. After 21 days, lethality was 14% after i.p. and 6% after s.c. administration. A total of 43 human tumours were tested for antineoplastic activity, 15 of which (36%) showed regression: 4/5 breast cancer xenografts, 1/3 colon, 1/1 gastric, 2/7 non-small-cell lung cancers (NSCLC), 3/4 small-cell lung cancers (SCLC), 1/2 sarcomas and 3/3 testicular cancers. Two ovarian, two uterine and six renal cancer xenografts as well as three melanomas and five tumours of various histologies were resistant. In 30 human tumour xenografts, the antineoplastic efficacy of the two oxazaphosphorine derivatives cyclophosphamide and IFO was compared. The maximum tolerated dose of cyclophosphamide was 200 mg/kg per day given i.p. on days 1 and 15; it led to 17% lethality after 21 days. Cyclophosphamide induced tumour regression or remission in 10/30 xenografts (33%) and IFO in 13/30 (43%). In conclusion, the observed efficacy of IFO parallels the clinical situation. Breast, lung and testicular cancer and sarcomas proved to be responsive. The antitumoural activity of IFO shows similarities to that of cyclophosphamide; however, a higher response rate and lower toxicity were noted for the former. Preclinical phase II studies in nude mice seem to offer an effective way of identifying active drugs as well as sensitive tumour types for further clinical development.
Asunto(s)
Ifosfamida/uso terapéutico , Neoplasias Experimentales/tratamiento farmacológico , Animales , Ciclofosfamida/uso terapéutico , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos , Femenino , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Humanos , Ifosfamida/toxicidad , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Trasplante HeterólogoRESUMEN
Mitosenes of both the pyrrolo- and pyrido[1,2-a]indole type have been prepared via modification of these heterotricyclic compounds. Several mitosenes have been studied for their reactions with nucleophiles under reductive conditions. The results of these experiments show that the biological activity of mitosenes is based on the mechanism of bioreductive activation. When both leaving groups at C-1 and C-10 in the mitosene are the same, the nucleophile preferably adds to C-10 under reductive conditions. All mitosenes were studied for their biological activities in vitro against L1210, WiDr, and A204. On the basis of these results a selection of three mitosenes was made for a more detailed biological evaluation. Several tumor model systems were used, viz. P388, human tumor xenografts, MAC 13, and MAC 16. The results of these studies show that mitosenes have a more limited range of activities than mitomycin C. Surprisingly, the in vivo activities of mitosene diol 8b and mitosene diacetate 10b against the gastric human tumor xenograft GXF 97 were very high and comparable with that of mitomycin C.
Asunto(s)
Antineoplásicos , Animales , Antineoplásicos/síntesis química , Fenómenos Químicos , Química , Femenino , Humanos , Leucemia L1210/patología , Ratones , Ratones Desnudos , Mitomicina , Mitomicinas/farmacología , Trasplante de Neoplasias , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
CGP 6809 [ethyl-6-deoxy-3,5-di-O-methyl-6-(3-methyl-3-nitrosoureido)-alpha-D- glucofuranoside] is a new methylnitrosoureido-sugar derivative that has been shown to be active against a broad spectrum of transplantable tumours in mice and rats. We investigated the anti-tumour effect of CGP 6809 in ten selected, human tumour xenograft lines growing s.c. in nude mice. The p.o. administration of 125 mg/kg per day for 10-15 days was less toxic (lethality 12% in tumour-bearing nude mice) than the i.p. injection of 62.5 mg/kg per day (lethality 22%). The anti-tumour effect was similar for both application routes; two large bowel cancers responded to treatment with CGP 6809, rectal cancer CXF 158 showed a remission, and the rapidly growing, undifferentiated colonic cancer CXF 280 exhibited a transient no-change. Furthermore, remissions were observed in the epidermoid lung cancer LXF 322 and in thyroid cancer 117. Tumour progression was found in another epidermoid lung cancer and in three stomach cancers, one melanoma, and one soft tissue sarcoma. CGP 6809 is a promising new agent for clinical trials, especially for large bowel and epidermoid lung cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Compuestos de Nitrosourea/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Trasplante HeterólogoRESUMEN
Screening for cytotoxicity in the clonogenic assay in human tumor xenografts and L1210 mouse leukemia revealed comparable dose-dependent effects of the alkyl lysophospholipid ET-18-OCH3 and the thioether lipid BM 41.440. The efficacy in human tumors only was marginal at low doses. In vivo tests of both agents were carried out in nude mice bearing two of the tumors that proved most sensitive in vitro and in mice inoculated with L1210 leukemia. Only small effects on the growth of the human tumors and no effects on L1210 leukemia were observed. In view of clinical rules for definition of remission, no convincing antitumor effects were obtained.