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1.
J Natl Cancer Inst ; 70(3): 499-504, 1983 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-6187963

RESUMEN

Adenosine (Ado) and Ado analogues produce multiple hemodynamic effects including coronary vasodilation, bradycardia, alterations in left ventricular contractility, and peripheral vasodilation or vasoconstriction depending on the vascular bed. The intact anesthetized Sprague-Dawley rat was examined in relation to electrocardiogram and blood pressure alterations induced by a series of potentially useful antineoplastic agents that are purine or pyrimidine analogues as part of a preclinical evaluation of these agents. The drugs tested were arabinosyladenine and its 5'-monophosphate derivative arabinosyladenine-5'-monophosphate (ara-AMP), the 2-fluoro derivative of ara-AMP, the pyrazolo[4,3-d]pyrimidines (formycin and formycin B), 8-azaadenosine, 6-methylmercaptopurine riboside, tricyclic nucleoside-5'-monophosphate, 5-fluorouracil, arabinosylcytosine, and 3-deazauridine. Those Ado analogues subject to deamination by adenosine deaminase (ADA) were also studied in the intact Sprague-Dawley rat after pretreatment with the ADA inhibitor 2'-deoxycoformycin. The results indicate that these agents have significant hemodynamic effects and should alert clinicians to potential adverse reactions when infusing these drugs.


Asunto(s)
Antineoplásicos/toxicidad , Hemodinámica/efectos de los fármacos , Hipotensión/inducido químicamente , Adenosina/análogos & derivados , Adenosina/toxicidad , Inhibidores de la Adenosina Desaminasa , Animales , Coformicina/análogos & derivados , Coformicina/farmacología , Relación Dosis-Respuesta a Droga , Electrocardiografía , Femenino , Formicinas/toxicidad , Pentostatina , Ratas , Ratas Endogámicas , Fosfato de Vidarabina/análogos & derivados , Fosfato de Vidarabina/toxicidad
2.
J Natl Cancer Inst ; 71(5): 933-9, 1983 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-6580495

RESUMEN

The occurrence of diffuse hyperpigmentation secondary to a xenografted human malignant melanoma was observed in nude mice. The patient from whom this cell line was established developed cutaneous hyperpigmentation after his disease became disseminated. Light and electron microscopy studies were performed on skin and organ biopsy specimens from the hyperpigmented mice. These studies indicated that this melanoma-associated melanosis was secondary to the release of pigment granules from the xenografted tumors and to the uptake of these granules by macrophages throughout the body, including those located in the dermis.


Asunto(s)
Melanoma/patología , Melanosis/etiología , Adulto , Animales , Modelos Animales de Enfermedad , Humanos , Hígado/patología , Metástasis Linfática , Masculino , Melaninas/orina , Melanoma/ultraestructura , Melanoma/orina , Ratones , Ratones Endogámicos , Ratones Desnudos , Trasplante de Neoplasias , Piel/patología , Pigmentación de la Piel
3.
Cancer Res ; 42(12): 5018-22, 1982 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-7139607

RESUMEN

The effects of N,N-dimethylformamide (DMF) and N-methyl-formamide (NMF) on the growth of two human colon cancer cell lines xenografted in nude mice were assessed. Toxicological studies with mice heterozygous for the nu/nu gene showed that with both compounds the limiting organ toxicity was hepatic. The 10% lethal doses for DMF and NMF given i.p. daily for 21 days were 2219 and 374 mg/kg, respectively. Nude mice (10/group) received s.c. transplants of HCT-15 or DLD- 2 human colon cancer cells. Mice were treated i.p. with the approximate 10% lethal doses of either DMF (daily for 21 days) or NMF (daily for 19 days) or with 0.9% NaCl solution when tumors became palpable. With the HCT-15 tumor, a growth inhibition of 65% was obtained using DMF compared to 0.9% NaCl solution-treated controls. Two independent experiments with DLD-2 demonstrated that DMF effected growth inhibitions of 45 and 67%. NMF treatment produced 48 and 75% growth inhibitions of HCT-15 and DLD-2 tumors, respectively. Weight loss of groups of treated mice in all experiments was between 2 and 14%, within the acceptable range for 10% lethal drug doses. Results indicate that some human cancer xenografts respond to the polar solvent DMF and to its metabolite NMF and that DMF may be acting at least in part by its metabolism to NMF. Furthermore, the data should alert clinical investigators to the possibility of hepatotoxicity when polar solvents are tested in Phase I clinical trials.


Asunto(s)
Neoplasias del Colon/fisiopatología , Dimetilformamida/farmacología , Formamidas/farmacología , Solventes/farmacología , Animales , División Celular/efectos de los fármacos , Línea Celular , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Trasplante Heterólogo
4.
Cancer Res ; 43(4): 1733-40, 1983 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-6831418

RESUMEN

The chicken chorioallantoic membrane was used to select variant tumor cell subpopulations from the murine melanoma B16-BL6 and the rat glioma C6 cell lines. Tumor cells were deposited on the chicken chorioallantoic membrane of eggs 10 days postfertilization. Upon hatching, chickens were autopsied, and organs were removed, minced, and implanted s.c. in C57BL/6J mice (for melanoma) or nude mice (for glioma). A glioma growing s.c. from a chicken lung implant metastasized to the liver of the recipient nude mouse, and a melanoma growing s.c. from a chicken liver implant metastasized to the lung of its murine host. The s.c. melanoma contained distinct black and gray areas. Cell lines were established from the s.c. glioma (C6-V-1), from a metastasis of the C6-V-1 tumor (C6-V-2), and from the black and gray regions of the melanoma. Marked differences in lung colonization were seen 14 days after 1 X 10(5) parent BL6, Black, or Gray cultured cells were injected by tail vein into C57BL mice. In four separate experiments, fewer than 15 lung foci per mouse were found when BL6 cells were injected, whereas 100 to several hundred lung melanoma colonies per mouse were observed when Black or Gray cells were inoculated. Four of 18 nude mice bearing the s.c. C6-V-1 glioma developed liver metastases; no metastases have been observed in 15 nude mice bearing the s.c. parent C6 glioma. Significant differences in sensitivities to antineoplastic drugs were demonstrated between parent and variant glioma cell lines. The 33-fold increase in sensitivity to vincristine determined for C6-V-1 cells compared to parent C6 cells was particularly striking. Results suggest that the use of the chicken chorioallantoic membrane in situ, together with the nude mouse, might provide a method suitable for the selection and isolation of aggressive variants in heterogeneous human tumors.


Asunto(s)
Variación Genética , Glioma/genética , Melanoma/genética , Alantoína , Animales , Línea Celular , Embrión de Pollo , Corion , Glioma/fisiopatología , Melanoma/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Metástasis de la Neoplasia , Neoplasias Experimentales/fisiopatología , Ratas
5.
Cancer Res ; 43(8): 3828-35, 1983 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-6861147

RESUMEN

Two separate cell lines originating from distinct metastatic deposits in a patient with a primary colonic carcinoma have been established both in vivo and in vitro. One metastasis, OM-1, was found in the omentum, and the other, HOT-3, was located on the ovary. These two metastases differ in several significant characteristics, including growth kinetics and the production of carcinoembryonic antigen by the cultured cells. OM-1 xenograft tumors contain about 8-fold more colonic mucin antigen than do HOT-3 heterografts. Similarities also exist. Both cell lines contain extra chromosomes in the A group, and both are missing chromosomes in Pair 14 of the D group and in Pair 18 of the E group. Xenograft tumors from these two metastases contain equivalent amounts of carcinoembryonic antigen and nonspecific cross-reacting antigen. These metastases developed through a process of progression and natural selection that occurred during the course of the patient's disease. Thus, the cell lines established from them provide material which may be used to study functional intraneoplastic diversity.


Asunto(s)
Neoplasias del Colon/patología , Antígenos de Neoplasias/análisis , Antígeno Carcinoembrionario/análisis , Línea Celular , Femenino , Humanos , Cariotipificación , Persona de Mediana Edad , Metástasis de la Neoplasia , Trasplante de Neoplasias , Trasplante Heterólogo
6.
J Clin Oncol ; 2(3): 227-41, 1984 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-6321692

RESUMEN

It has been known for many decades that certain murine and human cancers can spontaneously mature to benign tissue. These observations have stimulated investigators to attempt to induce a state of more normal or benign differentiation in cancer cells using biologic substances or chemicals. Polar solvents including dimethylsulfoxide, dimethylformamide, and monomethylformamide have proven to be good inducers of maturational events in murine and human cancer cells. Moreover, several laboratories have demonstrated that polar solvents inhibit the growth of human tumor xenografts in nude mice. These findings have resulted in the entry of monomethylformamide into phase I clinical trials in America and Europe. Preclinical work further suggests that polar solvents may be useful agents in combination with conventional treatment modalities. The use of drugs such as monomethylformamide that can convert neoplastic cells to benign cells rather than kill the tumor cells represents an important conceptual departure from standard cytotoxic chemotherapy. The use of maturational-agent therapy should be considered as an important new development in the design of cancer treatment protocols.


Asunto(s)
Antineoplásicos , Dimetilsulfóxido/uso terapéutico , Dimetilformamida/uso terapéutico , Leucemia Experimental/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Solventes/uso terapéutico , Animales , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular , Terapia Combinada , Evaluación de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Virus de la Leucemia Murina , Leucemia Experimental/genética , Leucemia Experimental/patología , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias/genética , Neoplasias/patología , Oncogenes
7.
J Clin Oncol ; 1(8): 496-509, 1983 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-6366142

RESUMEN

Heterogeneity within malignant neoplasms, although described for many years by pathologists, has only recently been extensively studied in the laboratory. It is now accepted that most tumors are composed of subpopulations of cells that differ in many phenotypic characteristics including the ability to form a metastasis. Cells with the capacity to metastasize are the ones most likely to prove lethal to the patient since clinicians can often control the primary neoplasm with surgery or radiotherapy. In this report the process of metastasis is discussed, those aspects of tumor cell heterogeneity that are relevant to this process are reviewed, intrapatient tumor heterogeneity is explored, and future preclinical studies are evaluated that may be useful in designing treatment strategies for patients with disseminated malignancies.


Asunto(s)
Metástasis de la Neoplasia , Neoplasias/patología , Animales , Antígenos de Neoplasias/análisis , División Celular , Neoplasias del Colon/patología , Humanos , Neoplasias Pulmonares/secundario , Metástasis Linfática , Ratones , Neoplasias/inmunología , Células Neoplásicas Circulantes
8.
Clin Pharmacol Ther ; 44(5): 501-9, 1988 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-3263248

RESUMEN

Clinical, pharmacologic, and immunologic effects of 2'-deoxycoformycin (dCF) were evaluated in 15 patients with advanced malignancies. Toxicity was less severe with a low dose (4 mg/m2) of dCF, but this dose still resulted in suppression of cellular adenosine deaminase activity, skin test reactivity, and lymphocyte responses to mitogens. Improvement in cutaneous T cell lymphoma plaques was seen after dCF. Further investigations of antitumor efficacy with the use of this low dosage schedule should continue in patients with hematologic neoplasms, and additional preliminary studies of the combination of an adenosine deaminase inhibitor with an adenosine analog should also be considered.


Asunto(s)
Inhibidores de la Adenosina Desaminasa , Antineoplásicos/efectos adversos , Coformicina/efectos adversos , Inmunosupresores/efectos adversos , Neoplasias/tratamiento farmacológico , Nucleósido Desaminasas/antagonistas & inhibidores , Ribonucleósidos/efectos adversos , Adenosina Desaminasa/metabolismo , Adulto , Anciano , Coformicina/administración & dosificación , Coformicina/análogos & derivados , Coformicina/uso terapéutico , Femenino , Humanos , Inmunidad/efectos de los fármacos , Masculino , Persona de Mediana Edad , Neoplasias/enzimología , Neoplasias/inmunología , Pentostatina
9.
Am J Med ; 71(6): 949-56, 1981 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-7315857

RESUMEN

The human colon carcinoma cell line DLD-1, established from tumor tissue obtained from a 45 year old white man with an adenocarcinoma of the sigmoid colon, was studied from the perspective of tumor heterogeneity. The karyotype and morphology of cells from an early passage DLD-1 culture, as well as the histologic features of both the original tumor and neoplasms produced by inoculation of athymic nude mice with DLD-1 cells, indicated that both the DLD-1 cell line and the original tumor were heterogeneous. Two clones were isolated from the DLD-1 line; they differed in their morphology, karyotype, and cloning efficiency in soft agar. Furthermore, when cells from each clone were injected into athymic mice, histologically distinct tumors were produced. Various analyses showed that the two cloned lines were representative of the two subpopulations predominantly responsible for the heterogeneity of the original neoplasm. In vitro drug screening results demonstrated that the two cloned lines have differential sensitivities to chemotherapeutic agents. The parent DLD-1 human colon carcinoma cell line and its two cloned subpopulations provide material for the study of various aspects and implications of human cancer cell heterogeneity.


Asunto(s)
Adenocarcinoma/patología , Neoplasias del Colon/patología , Adenocarcinoma/genética , Animales , Antineoplásicos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Células Clonales , Neoplasias del Colon/genética , Evaluación Preclínica de Medicamentos , Humanos , Técnicas In Vitro , Cariotipificación , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Fenotipo
10.
Int J Radiat Oncol Biol Phys ; 9(8): 1209-12, 1983 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-6409855

RESUMEN

Mice hosting a heterogeneous human colon xenograft tumor produced by subcutaneous injection of the DLD-1 tumor cell line were treated either with x irradiation alone, with mitomycin C alone (4 mg/kg), or with x irradiation given two hours after intraperitoneal injection of mitomycin C (4 mg/kg). Radiation alone produced a dose dependent delay in the time needed for tumors to regrow to twice their size at the time of irradiation, and in the mice receiving mitomycin C plus x irradiation, an additional growth delay equivalent to that produced by 3-3.5 Gy of X rays was seen at all X ray dose levels. As the DLD-1 tumor xenografts do not appear to possess a significant hypoxic fraction, we conclude that the two agents are acting in a simple additive cytotoxic manner by the killing of oxic tumor cells.


Asunto(s)
Adenocarcinoma/terapia , Antibióticos Antineoplásicos/administración & dosificación , Neoplasias del Colon/terapia , Mitomicinas/administración & dosificación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Animales , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/radioterapia , Humanos , Ratones , Ratones Desnudos , Mitomicina , Trasplante de Neoplasias , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/radioterapia , Trasplante Heterólogo
11.
Biochem Pharmacol ; 31(14): 2415-21, 1982 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-6982043

RESUMEN

The toxicology and metabolism of 8-azaadenosine (8-azaAdo) were examined both as a single agent and in combination with the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF). The LD10 (mice) for 8-azaAdo alone on a once daily for 5 days (q.d. x 5) schedule was 30 mg . kg-1 . day-1. When the animals were pretreated with 0.1 mg . kg-1 . day-1 of dCF, the LD10 dose was reduced to 10 mg . kg-1 . day-1 x 5. The major organ toxicity seen was hepatic. Bone marrow cellularity was only slightly altered at the LD10 dose. 8-AzaAdo nucleotides were detected in the livers of treated mice as determined by high performance liquid chromatography. Further, after 2 hr of incubation, isolated rat hepatocytes accumulated 8-azaATP to levels of 2.2 mumoles/g of cells with 8-azaAdo (1 mM) alone and to 4.3 mumoles/g of cells when 8-azaAdo was used in combination with dCF (1 microgram/ml). ATP levels decreased to below the limits of detection after 2 hr in cells treated with the combination. The replacement of cellular ATP by 8-azaATP may provide an explanation for the hepatotoxicity observed in the murine toxicology studies.


Asunto(s)
Adenosina/análogos & derivados , Coformicina/farmacología , Ribonucleósidos/farmacología , Adenosina/metabolismo , Adenosina/toxicidad , Animales , Análisis Químico de la Sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Coformicina/análogos & derivados , Interacciones Farmacológicas , Femenino , Dosificación Letal Mediana , Recuento de Leucocitos , Hígado/patología , Masculino , Ratones , Pentostatina , Ratas , Timo/fisiología
12.
J Anal Toxicol ; 8(3): 146-8, 1984.
Artículo en Inglés | MEDLINE | ID: mdl-6738004

RESUMEN

This report describes a gas chromatographic procedure, utilizing a packed column and flame ionization detector, suitable for the quantitative measurement of N-methylformamide (N-MF) in tissue samples. N-MF is a polar solvent that induces the maturation of cancer cells in vitro and, in vivo, exhibits antitumor activity with human tumors xenografted in nude (athymic) mice. Therapeutic monitoring is essential as toxicology studies have shown this compound to be hepatotoxic. N-MF is currently undergoing phase 1 clinical trials as an anticancer drug. This method of tissue analysis was developed to aid in the understanding of N-MF disposition and distribution in a murine model. The data thus generated may help predict the clinical behavior of this drug.


Asunto(s)
Antineoplásicos/metabolismo , Formamidas/metabolismo , Animales , Cinética , Ratones , Distribución Tisular
13.
J Anal Toxicol ; 7(2): 89-91, 1983.
Artículo en Inglés | MEDLINE | ID: mdl-6855210

RESUMEN

This report describes a gas chromatographic procedure using a packed column and a flame ionization detector, which is suitable for the therapeutic monitoring of N-methylformamide (N-MF). N-MF is a polar compound that induces cancer cell maturation in vitro and exhibits antitumor activity with human tumors xenografted in nude mice. Toxicology studies with mice have shown this compound to be hepatotoxic. N-MF is currently undergoing Phase I clinical trial as an anticancer drug at this institution. In concert with its clinical trial, a method for the analysis of N-MF in biological fluids has been developed to study its pharmacokinetics. This method involves direct injection of urine or acetone-deproteinized serum onto a Chromosorb 103 column, using N,N-diethylformamide as an internal standard.


Asunto(s)
Formamidas/análisis , Cromatografía de Gases , Formamidas/sangre , Formamidas/orina , Humanos
15.
Cancer Treat Rep ; 70(10): 1199-203, 1986 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-3530447

RESUMEN

In a randomized study 115 postmenopausal women with advanced breast cancer who were estrogen receptor-unknown or -positive were treated initially with tamoxifen or diethylstilbestrol (DES). Their pretreatment characteristics showed no significant difference. The frequency of response was identical with tamoxifen and DES, showing a complete response rate of 2% versus 2% and a partial response rate of 4% versus 8%, respectively; stable disease was present in 78% versus 73% of the patients, respectively. The median time to disease progression (5 vs 6 months) and median survival depending on initial hormone therapy (34 vs 35 months) were identical for tamoxifen and DES, respectively. Gastrointestinal toxicity was more frequent and more severe with DES than tamoxifen. Responses were seen with withdrawal of each agent and on crossover to the alternative agent. Our conclusions are that: DES and tamoxifen are equally effective in treating metastatic breast cancer in the postmenopausal patient who is estrogen receptor-positive or -unknown; withdrawal and crossover responses are seen with both agents; side effects are minimal but more frequent with DES; and on the basis of cost-effectiveness DES is the preferable agent.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Dietilestilbestrol/uso terapéutico , Receptores de Estrógenos/análisis , Tamoxifeno/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Ensayos Clínicos como Asunto , Dietilestilbestrol/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Distribución Aleatoria , Tamoxifeno/efectos adversos
16.
Med Oncol Tumor Pharmacother ; 5(2): 113-6, 1988.
Artículo en Inglés | MEDLINE | ID: mdl-3412035

RESUMEN

6-Methylmercaptopurine riboside (MMPR) and 5-fluorouracil (5-FU) were administered sequentially to 12 patients in a phase I clinical trial. Toxicities included mild nausea and vomiting, as well as reversible leukopenia and thrombocytopenia. Maximal accumulation of 6-methylmercaptopurine ribonucleoside 5'-monophosphate (MMPR-P), the active metabolite of MMPR, in patients' erythrocytes occurred between 2 and 6 h after the administration of MMPR and the degree of accumulation was dose-related. At 96 h after MMPR administration, MMPR-P was still detectable in patients' erythrocytes. Although no clinical responses were documented, a modified dosage schedule of these drugs should be pursued based on the pharmacokinetic data obtained.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Fluorouracilo/administración & dosificación , Inosina/análogos & derivados , Metiltioinosina/administración & dosificación , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Evaluación de Medicamentos , Quimioterapia Combinada , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/farmacocinética , Humanos , Masculino , Metiltioinosina/efectos adversos , Metiltioinosina/farmacocinética , Persona de Mediana Edad
17.
Cancer Treat Rep ; 67(3): 267-74, 1983 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-6600968

RESUMEN

The toxicology and pharmacology of formycin both as a single agent and combined with the adenosine deaminase inhibitor 2'-deoxycoformycin (dCF) were examined in outbred Swiss mice heterozygous for the nude gene (nu/+). The LD10 for formycin alone given on a daily x 5 schedule was 21 mg/kg. When the animals were pretreated with 1 mg/kg of dCF 1 hour prior to each dose of formycin, toxicity was approximately doubled, ie, LD10 was reduced to 10 mg/kg. Death was associated with hepatic toxicity in both treatment regimens; suppression of leukocyte counts was mild except at doses greater than the LD10. Formycin nucleotides were detected by high-performance liquid chromatography in the livers of mice treated with formycin either alone or combined with dCF. When isolated rat hepatocytes were incubated for 2 hours with either formycin or dCF plus formycin, analog nucleotides accumulated in the cells. Cellular ATP decreased to below the limits of detection, whereas a large peak corresponding to formycin-5'-triphosphate was present. This replacement of cellular ATP by formycin-5'-triphosphate may help explain the hepatic toxicity observed.


Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Coformicina/toxicidad , Formicinas/toxicidad , Ribonucleósidos/toxicidad , Inhibidores de la Adenosina Desaminasa , Animales , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Glucemia/metabolismo , Nitrógeno de la Urea Sanguínea , Coformicina/análogos & derivados , Coformicina/farmacología , Creatina/sangre , Sinergismo Farmacológico , Femenino , Formicinas/farmacología , Dosificación Letal Mediana , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratones Mutantes , Ratones Desnudos , Pentostatina , Ratas
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