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Biomedical subjects

F L Meyskens

Publications and source records attributed to F L Meyskens.

At least 145 records · Page 8Linked to original sources
PubMed1986

Regression of aggressive laryngeal papillomatosis with 13-cis-retinoic acid (accutane).

Laryngeal papillomatosis often involves a relentless growth of papillomas on the vocal cords, requiring repeated excisions to maintain an adequate airway. Because of its antiproliferative effects on epithelial tissues, 13-cis-retinoic acid (0.5-2.0 mg/kd/day p.o.) was used in five patients whose disease was poorly controlled by laser beam surgery. Control of disease for 24+, 5+, and 12 months has been achieved in three of the patients, with two complete and one partial responses. Side effects of treatment were mild and rapidly reversible, following a 25-50% reduction in drug dose.

Adult↗
PubMed1986

Phase II trial of beta-all-trans-retinoic acid for cervical intraepithelial neoplasia delivered via a collagen sponge and cervical cap.

Retinoids are effective suppressors of the phenotypic development of cancer in many animal systems, whether the process is initiated by chemical, physical or viral carcinogens. Cases of cervical intraepithelial neoplasia are excellent for studying the effectiveness of retinoids as chemopreventive agents because the process can be closely followed by serial colposcopic and pathologic (cytology or biopsy) means and changes in the condition safely monitored. We have previously conducted a phase I study of trans-retinoic acid (Tretinoin) given topically by a collagen sponge and cervical cap. A dose of 0.372% was selected for phase II trial. We have treated 20 patients with topical retinoic acid, and a complete response with total regression of disease was obtained in 50%. Systemic and cervical side effects were mild and vaginal side effects moderate but tolerable. These results provide a clinical basis for a randomized, double-blind phase III study to definitely answer the question of whether retinoic acid is an effective chemopreventive agent for cervical cancer.

Animals↗
PubMed1985

Dexamethasone and zinc in combination inhibit the anchorage-independent growth of S-91 Cloudman murine melanoma.

Zinc inhibited the colony formation of Cloudman S-91 murine melanoma cells in a dose dependent manner with an ID50 of 3.4 ug/ml. Total inhibition of the melanoma colony-forming units occurred at a zinc concentration of 4.42 ug/ml. In the presence of dexamethasone the ID50 for zinc inhibition was reduced by 49% and total inhibition of anchorage-independent growth occurred at the achievable in vivo zinc concentration of 3.0 ug/ml. Dexamethasone and zinc in combination effected a greater than additive inhibition of the murine melanoma colony-forming units. Statistical evaluation of these results showed that zinc and dexamethasone interacted synergistically to inhibit the formation of murine melanoma colonies.

Animals↗
PubMed1985

Anchorage-independent growth of murine melanoma in serum-less media is dependent on insulin or melanocyte-stimulating hormone.

alpha-Melanocyte-stimulating hormone (MSH) is known to stimulate melanogenesis in murine melanoma, particularly in Cloudman S-91 melanoma cells. The effects of MSH and insulin on the proliferation of S91 murine melanoma cells have aroused controversy; in various reports, both hormones have been reported to either stimulate or inhibit murine melanoma growth. In our studies both MSH and insulin stimulated the colony-forming ability and the proliferative capacity of S-91 murine melanoma cells grown in soft agar with either serum-supplemented or serum-less medium. Unless insulin and/or MSH were present, Cloudman S-91 melanoma cells failed to clone in soft agar. The insulin effect was greater than that of MSH, and was more pronounced in serum-less than in serum-supplemented medium. The concurrent treatment of S91 melanoma cells with both MSH and insulin resulted in a greater increase in the total number of colonies formed than caused by treatment with either hormone alone. The combined MSH-insulin stimulation of anchorage-independent growth was specific, since the effect could not be mimicked by epidermal growth factor (EGF), gonadotropin-releasing hormone (GRH), luteinizing hormone (LH), nerve growth factor (NGF) or platelet-derived growth factor (PDGF). Therefore, MSH and insulin may be specific growth factors for murine melanoma cells.

Animals↗
PubMed1985

13-Cis-retinoic acid: pharmacology, toxicology, and clinical applications for the prevention and treatment of human cancer.

Retinoids, particularly 13-cis-retinoic acid, have shown great promise against a number of benign, but serious dermatological conditions. In animal models, 13-cis-retinoic acid functions is a potent antipromoter whether a cancer has been initiated by chemical, physical, or viral agents. Additionally, substantial antiproliferative activity of this compound has been demonstrated in vitro in many culture systems. Clinical activity noted against several types of skin malignancies has led to several investigations to determine the anticancer activity of 13-cis-retinoic acid. Response of a variety of preneoplastic and neoplastic lesions of epithelial histology has been demonstrated. The toxicity of 13-cis-retinoic acid largely reflects its tissue distribution with skin and subcutaneous side-effects limiting dose escalation. The pharmacology and pharmacokinetics of 13-cis-retinoic acid has been explored in a number of patients and a long terminal half-life demonstrated. This review will discuss 13-cis-retinoic acid as a good model for a biological response modifier.

Animals↗
PubMed1985

Stimulation of human metastatic melanoma colony-forming cells by an acid-sensitive factor in human platelet sonicate.

A human platelet sonicate was evaluated for its effects on the growth of human metastatic melanoma colony-forming cells in soft agar from cells in culture and from biopsies. The addition of platelet sonicate increased both cloning efficiency and proliferative capacity in that more and larger colonies were formed. In more detailed studies under growth-limiting conditions, melanoma cellular responses to known growth factors were compared to the activity found in the platelet sonicate. None of the growth factors tested either alone or in combination, including platelet-derived growth factor, epidermal growth factor, alpha-type transforming growth factor, and beta-type transforming growth factor, were capable of inducing melanoma colony formation to the 12-fold stimulation observed with the platelet sonicate. Treatment of platelet sonicate with dithiothreitol, trypsin, or acid resulted in loss of activity for human melanoma. Our results suggest that human platelets contain an acid-sensitive protein which can support the expression of the transformed phenotype of human melanoma, and this factor is distinct from acid-stable activities previously characterized from human platelets.

Animals↗
PubMed1985

Phase I-II study of 13-cis-retinoic acid in myelodysplastic syndrome.

Eighteen patients with myelodysplastic syndrome received 13-cis-retinoic acid (1.0-mg/kg/day starting dose with 0.5-mg/kg increment escalations) in a phase I-II trial. Two partial responses involving the erythroid series were observed in four patients with primary refractory anemia with ring sideroblasts. One of two patients with chronic myelomonocytic leukemia also achieved a partial response. No other responses were found in the remaining patients, which included eight with refractory anemia with excess blasts. In six patients drug toxicity necessitated termination of the trial. Four patients had unexpected drug-induced thrombocytopenia; three of these had low platelet counts before treatment. Two of the six patients had other toxic effects. Further studies are warranted to evaluate the effectiveness of 13-cis-retinoic acid in patients with refractory anemia with ring sideroblasts and chronic myelomonocytic leukemia. At moderate doses significant toxic effects, including thrombocytopenia, are not uncommon.

Anemia, Refractory↗
PubMed1985

Similar self-renewal properties for different sizes of human primary melanoma colonies replated in agar.

Clonogenic assays currently define colonies as multicellular growth units above an arbitrarily designated cutoff size rather than by the biological function of different-sized growth units. To define the cutoff size between clusters and colonies in terms of the biological function of the cells within the growth units, we directly measured the self-renewal and proliferative capacity of cells from different-sized melanoma colonies. Primary colonies formed from cells of two patients were removed, pooled according to size, and replated, and the frequency and size distribution of the secondary colonies were analyzed. Cells from primary melanoma colonies that resulted from four to eight population doublings had similar extensive proliferative and self-renewal characteristics. The results demonstrated that self-renewal was not limited to cells in large colonies and suggested that the cutoff may be below 16 cells/growth unit. These data support the use of relatively small multicellular growth units to define colonies and measure highly proliferative human melanoma tumor cells. In addition, these methods may allow the determination of the cutoff size for other tumor types in terms of the biological function of cells rather than arbitrarily designating a cutoff size.

Agar↗
PubMed1985

Clinical-biologic patterns of metastatic melanoma and their effect on treatment.

We have identified three distinct groups of patients with metastatic malignant melanoma that differ in their clinical behavior and responsiveness to therapy. These include a favorable group of patients with lymph node or skin metastases, an intermediate prognostic group with lung or bone metastases, and a poor prognostic group with brain or gastrointestinal involvement. These three groups differed in their predicted objective response to therapy, in their likelihood to achieve a complete remission, and in their median survival.

Analysis of Variance↗
PubMed1984

Identification and quantitation of intracellular retinol and retinoic acid binding proteins in cultured cells.

Although the mechanism whereby vitamin A mediates normal cell differentiation and inhibits tumor cell proliferation is unknown, intracellular receptor-like proteins for retinol and retinoic acid have been implicated in the molecular action of vitamin A. We have assayed these two binding proteins, cellular retinol binding protein (protein R) and cellular retinoic acid binding protein (protein RA), in the cytosolic fraction of various normal and tumor cells via sucrose density gradient centrifugation and saturation analysis. Employing charcoal separation of bound and free tritiated retinoid, the saturation analysis yields an approximate Kd for ligand binding and an estimate of the number of protein R and protein RA molecules per cell. Unique protein R and protein RA macromolecules sedimenting at 2 S with Kd values of 7-42 nM are detected in murine cells (1 degree epidermal, 3T6 fibroblasts and melanoma) and human neuroblastoma cells. Concentrations of the intracellular binding proteins range from 55 000 to 3 000 000 copies per cell. When one cell line (C-127 mouse mammary) is transformed by bovine papilloma virus, protein RA levels increase from undetectable to 193 000 copies per cell. Assessment of growth inhibition by 10(-6) M retinol or retinoic acid in the culture medium reveals that there exists a partial, but not absolute, correlation between the presence of protein R or protein RA and the antiproliferative effect of the particular retinoid in the tested cell lines. We conclude that the 2 S intracellular binding proteins for the retinoids are present in most vitamin A responsive cells, but may not be essential for biologic actions of the vitamin such as growth inhibition in monolayer culture.

Animals↗
PubMed1984

Oral isotretinoin therapy. Use in a patient with multiple cutaneous squamous cell carcinomas and keratoacanthomas.

An 83-year-old woman with multiple squamous cell carcinomas and keratoacanthomas of the legs was treated with orally administered isotretinoin (13 cis-retinoic acid). Complete regression of the tumors was noted during the initial six-month treatment period. In the subsequent 36 months, four new cutaneous tumors were excised. There have been no recurrences of lesions that regressed while the patient was receiving retinoid therapy.

Administration, Oral↗
PubMed1984

Kinetics of clonogenic melanoma cell proliferation and the limits on growth within a bilayer agar system.

Accurate descriptions of the kinetics of cell growth in semi-solid agar clonogenic systems have been difficult because the number of cells in colonies of different sizes is largely unknown. We stained and removed tumor cell colonies from agar, directly counted their cells, and established equations to quantitate the number of cells within colonies of different sizes. We used these equations to quantitate, in terms of cell number and volume, the total amount and kinetics of clonogenic cell proliferation from biopsies of human melanoma and cell lines of several different tumor types. Daily observations of cells in agar and serial photography indicated a 0- to 4-day delay in the onset of proliferation in agar followed by rapid growth and then abrupt cessation of proliferation. We quantified the extent of proliferation of cells from melanoma biopsies of seven patients and 11 cell lines after they were allowed to proliferate in agar until they stopped. Approximately 10% of cells divided one to five times while only 0.01% divided six to nine times. The total number of cells within the colonies at the end of growth was different while the total volume of cells within the colonies per plate was similar; approximately 10(9) microns 3 cellular volume per plate represents an upper limit for proliferation within the closed, nonrefed bilayer agar system. Previous replating studies using the same biopsy cells have shown that clonogenic melanoma cells can self-renew and have more proliferative capacity than that expressed during primary colony formation. Thus, the clonogenic assay only measured initial proliferative capacities. Furthermore, variable delays in the onset of proliferation may contribute to the heterogeneity of colony size within clonogenic assays.

Agar↗
PubMed1984

Relation of in vitro colony survival to clinical response in a prospective trial of single-agent chemotherapy for metastatic melanoma.

We have used the effect of therapeutic agents on clonogenic growth in agar to discriminate between active and inactive agents for malignant melanoma. We report a prospective study of single-agent chemotherapy for metastatic melanoma. Forty-five separate in vitro/in vivo correlative trials were conducted in 34 patients. A number of agents were used in these evaluations, including actinomycin D, Amsacrine, bisantrene, mitoxantrone, BCNU, vinblastine, vindesine, 5-fluorouracil, MGBG, etoposide, interferon, tamoxifen, and 13-cis-retinoic acid. At the "cut-off" concentration, a colony survival less than 30% was designated as "sensitivity" and greater than 30% as "resistance." Clinical sensitivity was designated to include complete, partial, and mixed responses and was predicted in eight of 18 trials (44%). Clinical resistance (nonresponse) was predicted correctly in 24 of 27 cases (89%). Using Fisher's exact test the association of in vitro and in vivo results was significant (P = .05). These results offer further support for the concept that clonogenic assays may help select useful agents for clinical trials in metastatic melanoma.

Antineoplastic Agents↗
PubMed1984

Quantitation of the number of cells within tumor colonies in semisolid medium and their growth as oblate spheroids.

The number of cells within tumor colonies has not been determined accurately in prior reports because, in all but small clusters, cells grow too closely and stacked to allow direct counting of cells by inverted microscopy. Therefore, we stained colonies formed in agar from 38 tumor cell samples of diverse histological origin, removed them with a micropipet, and directly counted the number of cells. The number of cells within colonies increased geometrically with colony diameter and inversely with the size of the cells within the colonies. The relationship can be described using linear regression: [In(no. of cells/colony) = 0.87 - 2.80 In (colony cell diameter) + 2.38 In (colony diameter)] which gave an R2 of 0.92. Measurements of colonies in agar showed that they grew as oblate spheroids rather than spheroids. In an average sample, 60-micron-diameter colonies contained eight to 10 cells; the range for the 38 samples was 1.2 to 48.5. These results precisely define colonies in terms of cell number. They allow calculation of the total number of cells formed from clonogenic cells, a more complete estimate of proliferation than conventional cloning efficiencies which only measure initial proliferation. Furthermore, because of the dependence on the size of the colony cells, if colonies are defined only by a specific diameter then they do not contain similar numbers of cells. Calculations which assume spherical colonies, rather than the oblate spheroid shape we found, greatly overestimate the number of cells within colonies. Our data can increase the accuracy of quantitation in the clonogenic system and thus improve the interpretation of the proliferation of clonogenic tumor cells.

Cell Count↗
PubMed1983

Effect of 13-cis-retinoic acid and 4-hydroxyphenyl-all-trans-retinamide on human tumor colony formation in soft agar.

We studied the effects of 13-cis-retinoic acid (13cRA) and 4-hydroxyphenyl-all-trans-retinamide (4HPR) on the proliferation of clonogenic human tumor colony-forming units (TCFU) from patient biopsies in soft agar. Continuous exposure (5 X 10(-6)M) to 13cRA and 4HPR reduced colony formation to less than 50% of control in 49% and 31% of cases, respectively. This suggests that these retinoids have antiproliferative activity against TCFU. Continuous exposure to 13cRA reduced the number of TCFU to 30% of control in 22.6% of cases while 4HPR reduced colony formation to less than 30% of control in only 10% of patients tested. Prospective in vitro/in vivo correlations for 13cRA indicated that clinical resistance was correctly predicted in 4 of 4 cases treated while clinical response was predicted in 2 of 2 cases (one minor and one partial response). These data suggest that retinoids may have modest antitumor effects and that inhibition of TCFU growth in vitro may be used to screen for such activity.

Agar↗