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W Bollag

Publications and source records attributed to W Bollag.

At least 37 records · Page 2Linked to original sources
PubMed1994

Cancer combination chemotherapy with retinoids: experimental rationale.

Retinoids, cytokines as well as 1,25-dihydroxyvitamin D3 and its analogs are all classes of compounds with pleiotropic actions. They inhibit proliferation in human transformed epithelial cell lines and induce differentiation in human transformed hemopoietic cell lines. In a murine model of tumor cell-induced angiogenesis all three classes of compounds inhibit the formation of new blood vessels, necessary for supplying the growing tumor with oxygen and nutrients. Combinations of compounds from the three different classes lead to higher efficacy than the compounds administered as single agents. The effects of combinations vary depending on the individual representatives of the three classes and on the particular test models used. Additive, synergistic and potentiating effects have been observed. The results obtained in experimental systems raise hope that combination therapy might be useful in the treatment of certain human neoplastic diseases.

Animals↗
PubMed1994

Combination 13-cis-retinoic acid and interferon alpha-2a in the therapy of solid tumors.

Preclinical data indicate that the combination of retinoids and interferons have synergistic antiproliferative and differentiating effects in some hematologic and solid tumor models. These observations have led to clinical trials in which 13-cis-retinoic acid (13cRA) 1 mg/kg/day was combined with interferon alpha-2a (IFN alpha) 3 or 6 x 10(6) U/day. The first two such trials produced exciting results: 50% response rate in patients with previously untreated stages IB-IVA cervix cancer and 68% in patients with advanced squamous cell skin cancer. These data led to a number of additional trials of the combination, but the high response rates seen in the initial cervix and skin trials have not been duplicated in the other squamous tumors tested (head and neck, lung, pretreated cervix). In addition, trials in two nonsquamous histologies were negative (lung and melanoma). However, the regimen was not always studied in an optimal population of previously untreated patients and the negative results in pretreated cervix patients point to the relevance of this consideration. Nevertheless, the observation that the combination of 13cRA and IFN alpha (both of which bind to specific receptors and change gene expression) is able to induce regression in advanced tumors, must be regarded as highly important. Key questions to be addressed include an understanding of the biologic mechanism of specific tumor sensitivity (why some squamous tumors and not others?), and mechanisms of resistance in sensitive tumor types (e.g. cervix). Such data may lead to trials targeted to tumor types with defined biologic features having a high liklihood of clinical benefit. In the meantime, studies integrating this combination with other active treatment modalities such as radiation is warranted in cervix and skin carcinomas.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Combination 13-cis-retinoic acid and interferon alpha-2a in the therapy of solid tumors.

Preclinical data indicate that the combination of retinoids and interferons have synergistic antiproliferative and differentiating effects in some hematologic and solid tumor models. These observations have led to clinical trials in which 13-cis-retinoic acid (13cRA) 1 mg/kg/day was combined with interferon alpha-2a (IFN alpha) 3 or 6 x 10(6) U/day. The first two such trials produced exciting results: 50% response rate in patients with previously untreated stages IB-IVA cervix cancer and 68% in patients with advanced squamous cell skin cancer. These data led to a number of additional trials of the combination, but the high response rates seen in the initial cervix and skin trials have not been duplicated in the other squamous tumors tested (head and neck, lung, pretreated cervix). In addition, trials in two non-squamous histologies were negative (lung and melanoma). However, the regimen was not always studied in an optimal population of previously untreated patients and the negative results in pretreated cervix patients point to the relevance of this consideration. Nevertheless, the observation that the combination of 13cRA and IFN alpha (both of which bind to specific receptors and change gene expression) is able to induce regression in advanced tumors, must be regarded as highly important. Key questions to be addressed include an understanding of the biologic mechanism of specific tumor sensitivity (why some squamous tumors and not others?), and mechanisms of resistance in sensitive tumor types (e.g. cervix). Such data may lead to trials targeted to tumor types with defined biologic features having a high likelihood of clinical benefit. In the meantime, studies integrating this combination with other active treatment modalities such as radiation is warranted in cervix and skin carcinomas.

Carcinoma, Squamous Cell↗
PubMed1993

Inhibition of tumor cell-induced angiogenesis by retinoids, 1,25-dihydroxyvitamin D3 and their combination.

Tumor-induced angiogenesis (TIA), i.e., the ability of transformed cells to stimulate new blood vessel formation is an important factor contributing to tumor growth and invasiveness. The antiangiogenic effect of the retinoids, all-trans retinoic acid, 13-cis retinoic and 9-cis retinoic acid, of 1,25-dihydroxyvitamin D3, and of their combinations were studied using an experimental system in vivo. TIA was induced in immunosuppressed mice by intradermal injection of the two human transformed keratinocyte lines, Skv-e2, harboring DNA of human papillomavirus (HPV) type 16, and HeLa, harboring HPV18 DNA. The three retinoids and 1,25-dihydroxyvitamin D3, when administered systemically to mice, before the angiogenesis assay significantly decreased TIA. Their combination led to a synergistic inhibition of TIA. These results provide the basis for the use of combination of retinoids and 1,25-dihydroxyvitamin D3 in treatment of neoplastic diseases.

Animals↗
PubMed1993

Retinoids.

This review highlights recent advances in understanding the mode of action of retinoids at the level of molecular and cellular biology in relation to the new clinical results achieved with retinoids in various malignancies. All-trans-retinoic acid has been established in the clinic as a first-line differentiation therapy for acute promyelocytic leukemia. Other retinoids, as single agents or in combination, generated interesting preliminary results in prevention of or therapy for various precancerous and cancerous lesions. These results are currently being corroborated in ongoing trials. Retinoids are emerging as a new class of anticancer agents with a new molecular target, offering new combination therapies.

Antineoplastic Agents↗
PubMed1993

Historical aspects of the oral use of retinoids in acne.

A number of investigations of the effects of vitamin A deficiency in animals and man and its treatment with natural products containing vitamin A were carried out in the twenties and thirties. In 1942, a clinical study in patients with acne treated with vitamin A yielded encouraging results. Further trials in the forties and fifties, trying to confirm the beneficial effect of oral vitamin A in acne, met with equivocal success. In the sixties, all-trans retinoic acid (tretinoin) became clinically available, and its topical efficacy in acne could be demonstrated. In 1971, oral tretinoin also was shown to be active in patients with acne. Coincidentally, the efficacy of oral 13-cis retinoic acid (isotretinoin) became evident in a series of unpublished studies in Europe. Then, in 1978, a trial carried out at the NIH, Bethesda, Maryland, yielded convincing evidence that isotretinoin is a potent new drug for the treatment of severe cystic acne. In 1982, isotretinoin was registered in the United States and one year later in Europe for the treatment of severe, recalcitrant, cystic acne. Since then, many thousands of patients suffering psychologically and physically from the severity of their disease have been treated successfully with this drug. However, the main concern of physicians prescribing isotretinoin has to focus on its potentially severe side effects, particularly its teratogenicity.

Acne Vulgaris↗
PubMed1992

Inhibition of proliferation by retinoids, cytokines and their combination in four human transformed epithelial cell lines.

Various combinations of retinoids and cytokines were examined for their synergistic effect on inhibition in proliferation of four human transformed epithelial cell lines, MCF7 (mammary carcinoma), SCC4, SCC15 and A431 (squamous cell carcinomas). Synergism depended on the cell line tested, to some degree on the specific retinoid but particularly on the type of cytokine used. IFN alpha had the widest spectrum of activity. IFN gamma, TNF-alpha, IL-1, EGF and TGF-beta also exerted a synergistic effect on proliferation inhibition in certain cell lines, whereas G-CSF was inactive. Association of retinoids and cytokines represents a new approach to antitumor chemotherapy.

Breast Neoplasms↗
PubMed1992

Retinoids in cancer prevention and therapy.

Retinoids are a class of compounds structurally related to vitamin A. In preclinical studies, all-trans retinoic acid (tretinoin), 13-cis retinoic acid (isotretinoin) and the aromatic retinoids etretinate and acitretin have preventive and therapeutic effects on carcinogen-induced premalignant and malignant lesions. Clinically, chemoprevention with isotretinoin and etretinate has been tested with some degree of success in such indications as basal cell carcinomas, squamous cell carcinomas, superficial bladder tumors and second primary tumors in patients with squamous cell carcinoma of the head and neck. Limited therapeutic success has also been achieved with retinoid treatment of precancerous and cancerous conditions of the skin, oral cavity, larynx, lung, bladder and vulva. Dramatic therapeutic effects have been observed in the treatment of acute promyelocytic leukemia with tretinoin, which leads to very high rate of complete remission. Excellent results were recently reported in the treatment of squamous cell carcinomas of the skin and cervix with a combination of isotretinoin and recombinant interferon alfa-2a (rIFN alfa-2a, Roferon-A). The mechanism of action of retinoids is through modulation of cell proliferation and differentiation. Retinoids vary in their capacity to induce differentiation and to inhibit proliferation in a series of human transformed hematopoietic and epithelial cell lines. Some cytokines potentiate the retinoid-induced cell differentiation and act synergistically with retinoids to inhibit cell proliferation. The pattern of synergism is dependent upon the combination and tumor cell line tested. The discovery of nuclear retinoid receptors has contributed substantially to the understanding of the mechanism of action of retinoids at the molecular level. Further understanding of the molecular biology of retinoids is expected to contribute to a rational design of new retinoids in the future, which in turn may result in improvements in the prevention and therapy of cancer.

Animals↗
PubMed1992

Antitumor action of retinoids: inhibition of tumor cell line-induced angiogenesis and prevention of tumors in mice.

Acitretin was shown to inhibit angiogenic response to the tumorigenic SKV cell line bearing HPV16 genome and to sarcoma L-1 cell line, both in vitro and in vivo systems. The lowered angiogenic response to tumor cells was independent of duration and timing of the application of acitretin to animals. Acitretin, but not etretinate, was also found to be effective in the prevention of sarcoma tumors in mice.

Acitretin↗
PubMed1991

Antiproliferative activity of retinoids, interferon alpha and their combination in five human transformed cell lines.

Tretinoin, isotretinoin and acitretin were examined for their capacity to modulate the proliferation of the cell lines: HL-60 (acute promyelocytic leukemia), MCF7 (mammary carcinoma), SCC4, SCC15 and A431 (squamous cell carcinomas). Retinoids inhibited proliferation to a varying extent in all 5 cell lines. The cytokine IFN alpha had a significant antiproliferative effect only on HL-60, SCC4 and SCC15. The combination of retinoids with IFN alpha led in all 5 cell lines to a more profound reduction in proliferation than either retinoids or IFN alpha alone.

Acitretin↗
PubMed1991

Potentiation of retinoid-induced differentiation of HL-60 and U937 cell lines by cytokines.

Retinoids varied in their capacity to induce differentiation in HL-60 cells in this order: Ro 13-6307, tretinoin, isotretinoin, acitretin and Ro 13-7410 (high to low). In contrast, retinoids lacking a polar carboxylic acid, such as temarotene and Ro 14-6113, were inactive. Various cytokines had no differentiation-inducing effect by themselves. However, the addition of cytokines to retinoids increased differentiation. Combined with tretinoin, cytokines increased differentiation in this order: interferon (IFN) gamma, granulocyte colony-stimulating factor, interleukin-1 alpha (IL-1 alpha), IL-4, tumour necrosis factor alpha and IFN-alpha. Combination of cytokines with isotretinoin, acitretin, Ro 13-7410, and Ro 13-6307 showed a similar pattern of potentiation to that of tretinoin. Temarotene or Ro 14-6113 did not induce differentiation, alone or with cytokines. Combinations of cytokines were not synergistic in the presence of retinoids; antagonism was even observed. In U937 cells, lower levels of differentiation-induction were observed. Potentiation of the differentiation-inducing effect of retinoids by cytokines might indicate a clinical differentiation therapy of tumours.

Cell Differentiation↗
PubMed1991

Retinoids and interferon: a new promising combination?

The retinoids: all-transretinoic acid (tretinoin), 13-cis retinoic acid (isotretinoin) and the aromatic retinoids etretinate and acitretin have a preventive and therapeutic effect on chemically-induced tumours. Clinically, retinoids have shown variable effectiveness in therapy and/or prevention of oncological diseases of skin, head and neck, lung, bladder, vulva and bone marrow. With a few exceptions, monotherapy with retinoids has not been satisfactory. Similarly, monotherapy with interferon alpha has been used successfully only for some specific indications. Retinoids have a marked differentiation-inducing effect which may contribute to their therapeutic effect. Experiments were carried out in transformed cell lines to test the combination of retinoids with interferon alpha and other cytokines on differentiation. In HL-60 cells, an acute promyelocytic leukaemia cell line, induction of differentiation was determined by induction of an oxidative burst potential. Retinoids showed the following order of activity: tretinoin greater than isotretinoin greater than acitretin. Cytokines had no differentiation-inducing effect by themselves. However, the addition of the following cytokines to retinoids potentiated the retinoid-induced differentiation: IFN alpha, IFN beta, IFN gamma, TNF alpha, G-CSF, IL-1 alpha and IL-4. In experiments with HL-60 or other cell lines, the pattern of differentiation-induction was always dependent on the particular retinoid/cytokine combination. IFN alpha provoked a marked potentiation of retinoid-induced differentiation. The combination of the antiproliferative and differentiation-inducing effect of the retinoids together with the antiproliferative, immunostimulatory and differentiation-potentiating effects of IFN alpha suggests that this combination might be a particularly promising treatment for neoplastic diseases.

Cell Differentiation↗
PubMed1991

Modulation of human immune functions in vitro by temarotene and its metabolite.

The arotinoid temarotene (Ro 15-0778) and its metabolite Ro 14-6113 were examined in a variety of in vitro assays quantitating parameters of human immune functions. Both immunosuppressive and immunostimulatory activities of these compounds were identified. These activities were compared with those of the known immunomodulatory compound ciclosporin A (CsA) at concentrations corresponding to clinically effective plasma concentrations. Like CsA, Ro 14-6113 inhibited the mitogen- or alloantigen-induced proliferation of T cells as well as their capacity to secrete interleukin-2 (IL-2), interferon-gamma and tumor necrosis factor alpha. Ro 15-0778 showed no activity in inhibiting cytokine secretion and was considerably less effective than Ro 14-6113 in inhibiting T cell proliferation. Ro 14-6113 was more effective than CsA in inhibiting IL-2 receptor expression. Ro 14-6113 modulated both positively or negatively the proliferation of B cells, depending on the concentration. Ro 14-6113 inhibited the secretion of IgM, IgG, and IgA, while stimulating IgE secretion. A different profile of activity for Ro 14-6113 and CsA was observed, suggesting differing effectiveness in immunologically mediated diseases.

B-Lymphocytes↗
PubMed1991

Parathyroid hormone modulates angiotensin II-induced aldosterone secretion from the adrenal glomerulosa cell.

The effect of PTH on aldosterone secretion from isolated bovine adrenal glomerulosa cells was examined. PTH binding was autoradiographically localized to the adrenal cortex, suggesting a specific effect. This binding of PTH was displaceable by cold PTH, but not by ACTH. No binding was observed in the adrenal medulla. In addition, PTH was shown to stimulate aldosterone secretion in a dose-dependent manner and to potentiate aldosterone secretion in response to angiotensin-II, such that PTH (10(-9)M) elevated the secretory rate from 58.6 +/- 6.8 to 110.9 +/- 19 pg/min.million cells in the presence of 10 nM angiotensin-II. The magnitude of the synergism between the two hormones depended on the concentrations of PTH and angiotensin-II as well as the time during which aldosterone secretion was measured. Within the first 15 min of stimulation, PTH increased the sensitivity to angiotensin-II, shifting the Ka for activation from 1.0 to 0.3 nM. In contrast, between 30-45 min of angiotensin-II stimulation, PTH elevated the maximal secretory response to angiotensin-II from 109 +/- 3.4 to 219 +/- 13.3 pg/min.million cells. By itself PTH elicited only a small increase in the intracellular Ca2+ concentration, as measured by aequorin luminescence in glomerulosa cells. In cells pretreated with angiotensin-II or 15 mM potassium, the intracellular calcium response to PTH was markedly potentiated. PTH was also found to cause a small increase in the cellular cAMP content. Thus, PTH stimulates aldosterone secretion from adrenal glomerulosa cells, both alone and in combination with angiotensin-II.

Adrenal Cortex↗
PubMed1990

The relevance of the mouse papilloma test as a predictor of retinoid activity in human psoriasis.

The combination of the results of mouse antipapilloma tests with those from hypervitaminosis A tests in mice as the basis for calculating a therapeutic index has been used for more than 20 years in the search for retinoids as useful drugs in human dermatology. A number of retinoids identified as active or inactive when administered systemically in these mouse systems have gone into clinical trials; clinical results on 11 retinoids were available for a retrospective analysis on the predictive relevance of the mouse models for retinoid activity in human psoriasis. This analysis revealed that the therapeutic index in mice correctly identified eleven compounds and differentiated them into markedly active, moderately active or inactive retinoids when subsequently used clinically in the treatment of various forms of psoriasis. Acidic retinoids were more difficult to assess than nonacidic ones and the therapeutic index appeared to underestimate their potency in humans. One retinoid, motretinide, showed a favorable therapeutic index but failed to demonstrate antipsoriatic activity in the clinic. The reason for this discrepancy is that humans and mice metabolize this compound differently. Thus, although chemically induced skin papillomas in mice reflect only certain analogies to human psoriasis and other keratinizing dermatoses, they may be considered a useful tool in the search for retinoids for the treatment of keratinization disorders.

Animals↗
PubMed1990

Calcium ion as intracellular messenger and cellular toxin.

Ca2+ serves a nearly universal intracellular messenger function in cell activation, but excess Ca2+ is also a cellular toxin. The possibility of Ca2+ intoxication is minimized by an elaborate autoregulatory system in which changes in Ca2+ influx rate across the plasma membrane are rapidly compensated for by parallel changes in Ca2+ efflux rate. By this mean, cellular Ca2+ homestasis is maintained so that minimal changes in total cell calcium and cytosolic Ca2+ concentration occur during sustained Ca2(+)-mediated responses. Rather than a sustained increase in cytosolic Ca2+ concentration, it is the localized cycling of Ca2+ across the plasma membrane that is the critically important Ca2+ messenger during the sustained phase of cellular responses mediated via surface receptors linked to the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). PIP2 hydrolysis gives rise to inositol(1,4,5)trisphosphate (IP3) and diacylglycerol (DAG). The IP3 acts to release Ca2+ from an intracellular pool, thereby causing a transient rise in cytosolic Ca2+ concentration. This transient Ca2+ signal activates calmodulin-dependent protein kinases transiently, and hence, causes the transient phosphorylation of a subset of cellular proteins that mediate the initial phase of the response. The DAG brings about the association of protein kinase C (PKC) with the plasma membrane where a receptor-mediated increase in Ca2+ cycling across the membrane regulates PKC activity. The sustained phosphorylation of a second subset of proteins by PKC mediates the sustained phase of the response. Hence, Ca2+ serves as a messenger during both phases of the cellular response, but its cellular sites of action, its mechanisms of generation, and its molecular targets differ during the initial and sustained phases of the response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗