tretinoin and Bone-Marrow-Diseases

In addition to suppressing breast cancer cell growth, retinoids potentiate growth inhibition in human breast cancer when tested in vitro and in vivo with tamoxifen and/or interferon. The purpose of this study was to ascertain the biologic effects of all-trans-retinoic acid (ATRA) administered alone and with tamoxifen +/- interferon and to identify the relationship between ATRA plasma concentrations and optimal biological dose (the lowest dose that produces a biological response). Three consecutive groups of 15 patients with locally advanced operable breast cancer were treated, in accordance with good clinical practice (GCP) requirements, with ATRA at 3 dose levels alone or with tamoxifen +/- alpha-interferon 2a at flat doses. After 3 weeks, the tumors were surgically removed. Biological parameters measured at the beginning (in biopsy tissue) and end (in surgical tissue) of the study were compared. The optimal biological dose for ATRA was 15 mg/m2/day. Treatments influenced tumor grade but not cell cycle kinetics (G0-G1 phase) or proliferation (Ki67 levels). ATRA induced progesterone receptors independent of dose level and co-administered drugs, but did not induce estrogen receptors when administered alone. Retinoic acid receptor (RAR)-alpha was not affected by treatment and RAR-alpha was moderately influenced whereas RAR-beta (concomitantly with transforming growth factor-beta) was induced in 33% of patients by ATRA alone. ATRA pharmacokinetics were dose- and time-dependent. Neither the ATRA + tamoxifen nor the ATRA + tamoxifen + interferon combinations potentiated the ATRA-induced biological changes. Future studies evaluating the role of RAR-beta as a biological marker of retinoid activity are warranted.

Topics: Aged; Aneuploidy; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bone Marrow Diseases; Breast Neoplasms; Carcinoma; Drug Administration Schedule; Drug Interactions; Female; Follow-Up Studies; Headache; Humans; Hypercholesterolemia; Interferon alpha-2; Interferon-alpha; Ki-67 Antigen; Mastectomy; Middle Aged; Neoplasm Proteins; Receptors, Retinoic Acid; Receptors, Steroid; Recombinant Proteins; Safety; Tamoxifen; Transforming Growth Factor beta; Transforming Growth Factor beta1; Treatment Outcome; Tretinoin

Numerous agents induce differentiation and maturation of neoplastic and dysplastic myeloid cells in vitro and some of these agents have been used with limited success in the treatment of patients with myelodysplastic syndromes (MDS) and myeloid leukaemias. We recently proposed that physiological and pharmacological agents which enhance differentiation and maturation in vitro act by two fundamentally different routes: (1) by hastening the progression through various differentiation/maturation steps; (2) by slowing proliferation (usually by inhibition of DNA synthesis). In order to test this thesis we looked for synergistic effects on differentiation using pairs of agents from the two groups in cultures of cells from myelodysplastic and acute myeloid leukaemia (AML) patients and from normal marrow donors. The results with three MDS, two AML and three normal samples show that combinations of differentiation inducing agents (retinoic acid, N-methylformamide) with DNA synthesis inhibitors (6-mercaptopurine, cytosine arabinoside and aphidicolin) produce a differentiation inducing effect equivalent to that of 10-100, or even 1000 fold higher concentrations of single agents. Myelotoxic effects in vitro were not synergistic. The use of these synergistic combinations should greatly enhance the usefulness of differentiation inducers in the therapy of MDS and myeloid leukaemia.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aphidicolin; Bone Marrow; Bone Marrow Diseases; Cell Differentiation; Cells, Cultured; Cytarabine; Diterpenes; DNA; Drug Synergism; Formamides; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Preleukemia; Syndrome; Tretinoin

Five retinoid analogues differ in their effects on the growth of CFU-GM from normal human marrow. At concentrations above 10(-6) M all have inhibitory activity. This is maximal with 13-cis-retinoic acid. At lower concentrations the effect of retinoids is usually to reduce clone size rather than clone numbers though 10(-8)-10(-7) M etretinate increases clone size. The incubation of marrow cultures in the presence of 10(-6) M all-trans retinoic acid showed that in normal subjects colony counts are never reduced to less than 45% of the control value and total clone counts to less than 70% of the control value. In cultures from patients with myelodysplastic syndrome 20 out of 34 cases showed a greater inhibition of colony numbers than normal and 14 out of 35 cases showed a greater reduction in total clone numbers than normal. The results suggest that CFU-GM from some patients with myelodysplastic syndrome may have a greater sensitivity than normal to the inhibitory effect of retinoic acid.

Topics: Adult; Aged; Bone Marrow; Bone Marrow Diseases; Cells, Cultured; Colony-Forming Units Assay; Depression, Chemical; Hematopoietic Stem Cells; Humans; Middle Aged; Retinoids; Tretinoin