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Biomedical subjects

M A Friedman

Publications and source records attributed to M A Friedman.

At least 19 recordsLinked to original sources
PubMed1992

Retinoids in the lateral eye of Limulus: evidence for a retinal photoisomerase.

The lateral eyes of the horseshoe crab Limulus contain about 80 pmoles of retinal, 30 pmoles of retinol, and 4 pmoles of retinyl esters. More all-trans than 11-cis isomer was found in each category of retinoid. No consistent changes were observed in the amounts of retinal, retinol, or retinyl esters as a function of time of day. No 3,4-dehydro- nor hydroxyretinoids were found. Aqueous extracts of the eye support the stereospecific formation of 11-cis retinal from all-trans retinal when irradiated with light. The reaction requires a protein that is apparently recognized by polyclonal antibodies raised against the retinal photoisomerase extracted from honeybee eyes. The isomerase is able to use as substrate either endogenous all-trans retinal in the extract of retinal supplied in vesicles of phospholipid. The spectral efficiency of this isomerization has lambda max at 550 nm, but the spectrum appears too narrow compared with the absorbance spectrum of retinoid-binding proteins, probably because of inadequate correction for nonspecific isomerization at short wavelengths.

Animals↗
PubMed1992

Retinoids in cancer therapy.

PURPOSE: Recent reports of the dramatic antitumor effect of all-trans retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have generated renewed enthusiasm for clinical studies of retinoids for oncologic therapeutic indications. Here we provide an overview of relevant aspects of retinoid physiology and molecular biology, review preclinical studies indicating antitumor activity for retinoids, and summarize the current status of clinical investigations of retinoid use for the treatment of adult and pediatric tumors. DESIGN: The published literature was reviewed with attention to areas of retinoid research that would shed insight into the oncologic uses of retinoids. RESULTS: Retinoids play critical roles during normal fetal development and induce differentiation (and/or growth inhibition) in a variety of tumor-cell lines. Retinoid effects seem to result from changes in gene expression mediated via specific nuclear receptors (termed retinoic acid receptors, RAR-alpha, -beta, and -gamma), and a specific chromosomal translocation involving the RAR-alpha gene occurs in APL patients. In addition to the very high clinical response rate for RA in patients with APL, significant clinical responses have been observed for patients with cutaneous T-cell malignancies, juvenile chronic myelogenous leukemia, and dermatologic malignancies. Additionally, the combination of 13-cis-retinoic acid (cRA) with interferon alpha (IFN alpha) has produced high objective response rates for patients with squamous cell carcinomas of the head and neck and of the cervix. CONCLUSIONS: The antitumor activity demonstrated for retinoids (especially RA) alone and in combination with other agents supports the need for targeted phase II trials to define the spectrum of responsive tumors and for laboratory studies to further delineate the biologic mechanisms associated with therapeutic responses. High priority should then be given to phase III trials to delineate optimal strategies for improving outcome by combining retinoid-based treatments with conventional chemotherapy and radiotherapy regimens.

Animals↗
PubMed1992

Trans-retinoic acid and related differentiation agents.

Interest in retinoids as therapeutic agents has developed as a result of the observations of remission induction with all-trans retinoic acid (tRA) in patients with acute promyelocytic leukemia (APL), and of high objective response rates noted with the combination of cis-retinoic acid (cRA) with interferon-alpha in squamous cell carcinomas of skin and cervix. The therapeutic experience with RA in APL is discussed in this article from the perspectives of new information concerning retinoid biology, observations related to the development of the retinoid syndrome, complex pharmacology of this agent, and possible explanations for development of retinoid resistance. The current National Cancer Institute-supported drug development strategy for RA used alone or in combination with other differentiating agents, and the potential therapeutic uses in cancer for other retinoids are also discussed.

Animals↗
PubMed1991

Thalamo-cortical processing of vibrissal information in the rat. I. Intracortical origins of surround but not centre-receptive fields of layer IV neurones in the rat S1 barrel field cortex.

The receptive fields of cells restricted to the D1 cortical barrel territory in the S1 cortex of the rat were examined before and after substantial lesions of the D2 barrel. We tested 131 cells (N = 62, unlesioned controls; N = 69, lesioned animals) for modal latency and response magnitude to standard vibrissal deflections of 1.14 degrees. Lesions ranged in size to encompass 22-95% of the volume of the D2 barrel hollow and 5-75% of its neighbouring septal region, as calculated from cytochrome oxidase and Nissl staining of alternate sections. Negligible loss (mean 1.1%) of other barrel hollows and their septal regions (6.3%) occurred. A mean loss of 58% of the D2 barrel hollow and 27% of its accompanying septa was paralleled by a highly significant deficit in response magnitude (57.3%; p less than 0.005) of D1 barrel cells to D2 vibrissal stimulation, when compared with controls. The best-fit relationship between deficit and volumetric loss of the D2 barrel hollow was linear (regression coefficient -0.91). In the extreme case where 95% loss of D2 barrel hollow occurred, there was a 92% deficit in response of D1 barrel cells to the D2 input. No significant loss in response magnitude to other vibrissae, including the principal D1 input, occurred. Postlesioned animals exhibited some increase in excitability to the D1 vibrissa, and to vibrissae whose principal barrel territories were undamaged (delta, gamma, C1). Lesioning of the D2 barrel caused a highly significant mean increase (60%) in latency of residual responses to stimulation of the D2 vibrissal input (15.2 ms controls; 24.3 ms experimentals). No significant changes in response latency to other vibrissae compared to controls occurred. These results suggest that an intact D2 barrel is essential for the generation of responses of D1 barrel cells by the D2 vibrissa, and further imply that surround receptive fields of layer IV barrel cells are largely generated intracortically by barrel-to-barrel relay. The implications of these findings to cortical processing of tactile information and plasticity in the somatosensory system are discussed.

Afferent Pathways↗
PubMed1991

Commentary concerning demonstration of safety and efficacy of investigational anticancer agents in clinical trials.

Expeditious clinical development and approval of new drugs that are beneficial to patients are matters of high priority. There has been a great deal of discussion within the oncology community about what should constitute evidence of effectiveness of new anticancer agents for purposes of drug approval. This commentary is intended to illustrate a variety of end points that can lead to approval of new anticancer agents for specific clinical situations. Although the ultimate hope of antineoplastic therapy is prolongation of life, there are other effects of anticancer drugs that constitute clear clinical benefit and represent evidence of effectiveness. The guiding principle is that the beneficial effects obtained from a new drug should sufficiently outweigh the adverse effects such that the potential risk:benefit ratio achieved by an individual patient is favorable. The assessment of a new drug should flexibly evaluate safety and efficacy in the context of the specific clinical condition being treated. Early discussions with the Food and Drug Administration (FDA) and the National Cancer Institute (NCI) are recommended to identify prospectively the end points and trial designs needed to demonstrate effectiveness of a new drug. The general principles discussed will likely apply to the drug approval process for other medical disciplines as well.

Antineoplastic Agents↗
PubMed1990

Opportunities in clinical trials. Adjuvant breast cancer.

Breast cancer is the most common cancer in women in the US, with approximately two-thirds of patients presenting with tumors confined to the breast alone or breast and ipsilateral axillary lymph nodes. Although all of these women can be rendered free of detectable breast cancer by local therapeutic modalities, many will experience recurrences regionally or at distant sites. Nearly all patients who have distant recurrences will subsequently die of breast cancer. Although metastatic breast cancer responds to a variety of hormonal and chemotherapeutic interventions, it is rare that such therapy is curvative. Hence, there has been great interest in studying adjuvant systemic therapies. There is now a long clinical trial experience with adjuvant therapy in breast cancer that provides an extensive background for implementing recent advances in molecular and cellular biology in the clinical setting. Predictably, these laboratory-clinical correlations will provide important leads for future generations of randomized adjuvant trials, both by helping to target new therapies for particular subsets of patients and by identifying prognostic groups. In this report, current efforts in adjuvant therapy trials and laboratory-clinical correlations being conducted in conjunction with those trials are described.

Breast Neoplasms↗
PubMed1990

The distribution of [14C]acrylamide in rainbow trout studied by whole-body autoradiography.

The distribution of [2,3-14C]acrylamide was studied in fingerling rainbow trout by whole-body autoradiography. Fish weighing approximately 7 g were injected ip with 3.2 mg/kg [14C]acrylamide (0.1 microCi/g). One group of fish was kept in a fresh flowing water tank and frozen in dry ice/hexane 22 hr after injection; another group was placed in a separate tank of fresh flowing water and frozen 120 hr after treatment. A third group of fish served as nontreated controls. The autoradiographs of the fish at 22 hr show the highest concentration of radioactivity in the kidney, urinary bladder, blood, gallbladder, intestinal contents, and lens of eye. Lesser amounts of radioactivity are seen in the CNS, liver, and gills. Very low concentrations are seen in muscle. By 120 hr the only high concentrations are seen in gallbladder and lens of the eye. Lesser amounts are seen in the sclera, vertebrae, CNS, kidney, wall of intestine, and discrete spots in subcutaneous tissue presumed to be chromatophores. Low amounts are seen in muscle, the tissue usually consumed by man.

Acrylamide↗