tretinoin and Hypertriglyceridemia

All-trans retinoic acid (ATRA), a potent differentiating drug for acute promyelocytic leukemia (APL), induces a high incidence of complete remission (CR) in patients with APL and is now established as a first-line therapy. However, ATRA resistance has become a clinical problem. Patients who relapsed after ATRA-induced CR have had difficulty in obtaining a second CR with ATRA therapy. Although several mechanisms have been postulated, treatment strategies to overcome resistance have not been established. We used a new synthetic retinoid, Am-80, as reinduction therapy for APL relapse after from ATRA-induced CR. Am-80 was several times more potent than ATRA in inducing differentiation in vitro. At a 6 mg/m2 dose, there were 24 evaluable patients; 14 (58%) achieved CR between days 20 and 58 (median, 37 days). Clinical response correlated with the in vitro response to Am-80. Adverse effects included retinoic acid syndrome (n = 1), hyperleukocytosis (n = 1), xerosis (n = 9), cheilitis (n = 8), hypertriglyceridemia (n = 16), and hypercholesterolemia (n = 15). Am-80 is active in APL after relapse from ATRA-induced CR. Further clinical trials are needed to establish strategies to overcome ATRA resistance.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Benzoates; Biomarkers, Tumor; Cheilitis; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Pilot Projects; Recurrence; Remission Induction; Salvage Therapy; Tetrahydronaphthalenes; Treatment Outcome; Tretinoin; Tumor Cells, Cultured

Although retinoids show promise for prevention of second primary upper aerodigestive tract tumors, the optimum retinoid, dose, and schedule are unknown. All-trans retinoic acid (ATRA) has greater affinity for retinoic acid receptors and may be more active than other retinoids but has a shorter plasma half life and may up-regulate its own metabolism. We defined the maximum long-term tolerable dose, dosing frequency, pharmacokinetics, and toxicity of ATRA in patients with treated squamous cell carcinoma of the head and neck (SCCHN). Twenty-one patients were randomized to 45, 90, or 150 mg/m2 ATRA either once daily, or as divided doses every 8 h, for 1 year. Pharmacokinetics were assessed periodically. Fourteen men and seven women with previous SCCHN of initial stage I-IV were treated. Grade > or =3 toxicities (reversible) included headache and hypertriglyceridemia in 5 and 6 patients each, mucositis in 2 patients, and hyperbilirubinemia, elevated alkaline phosphatase, colitis, lipasemia, xerostomia, eczema, and arthritis in 1 patient each. The 150-mg/m2 dose was not tolerable. Doses were reduced for grade > or =3 toxicity in seven of eight patients at 90 mg/m2 daily. Three of nine patients at 45 mg/m2/day required dose reduction, two at the once-daily dose. Day 1 ATRA area under the plasma concentration versus time curve (AUC) increased with dose, and after 1-2 months of continued dosing, the AUC declined in 7 of 13 patients (54%) studied. ATRA AUC did not correlate with toxicity severity or frequency. Fifteen mg/m2/day every 8 h is a tolerable dose for 1 year in patients with treated SCCHN. ATRA pharmacokinetics did not correlate with toxicity.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Exanthema; Female; Follow-Up Studies; Head and Neck Neoplasms; Headache; Humans; Hypertriglyceridemia; Male; Middle Aged; Mouth Mucosa; Neoplasm Staging; Stomatitis; Treatment Outcome; Tretinoin

Twenty-two patients with high-risk myelodysplastic syndrome (HRMDS) were treated with a 10-day course of oral all trans retinoic acid (45 mg/m2) and s.c. low-dose cytosine arabinoside (LDARAc) given at the dose of 20 mg twice per day. The courses were repeated monthly until response or progression, in the case of response, the therapy was administered until relapse. Morphologic diagnoses were refractory anemia with excess blasts (RAEB) in nine, RAEB in transformation (RAEB-t) in nine, and chronic myelomonocytic leukemia (CMMoL) in four patients; in all cases, bone-marrow blast infiltration was greater than 10% (median 20%, range 12-30%). When the international prognostic scoring system was applied, all the cases qualified as intermediate/high-risk categories. Nineteen patients were males and three were females; the median age was 69 years (range 25-90 years); three patients had previously been treated with conventional chemotherapy, and one of them had also undergone autologous bone-marrow transplantation. The criteria of response were defined as follows: (1) complete response: normalization of blood counts and bone-marrow blasts (<5%), and (2) partial response: decrease in bone-marrow blast infiltration by 50%, and two of the following parameters - improvement in hemoglobin level by 1.5 g/dl or decrease by 50% in transfusional requirement, increase by 50% in absolute neutrophil count, and increase by 50% in platelet count. Overall, 7 (32%) of 22 patients achieved a response, with 5 (23%) being classified as complete responders and 2 (9%) as partial responders. Fifteen (68%) patients did not achieve any response, and 14 died of progressive disease or infectious disease. The overall median survival was 8 months (range 1-27 months), whereas the median survival of responders was 16 months (range 8-27 months); the median duration of response was 11 months (range 2-21 months). Moderate to severe hematological toxicity and infections were the most common side effects. In conclusion, it seems that the association of ATRA and LDARA-C may be effective in approximately 30% of HRMDS patients. Optimizing this approach might be pursued by selecting, on a biological basis, those cases more likely to respond or by incorporating other differentiating agents or growth factors.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Cytarabine; Dose-Response Relationship, Drug; Female; Humans; Hypertriglyceridemia; Infections; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Thrombocytopenia; Tretinoin

All-trans retinoic acid (ATRA), a potent differentiating drug for acute promyelocytic leukemia (APL), induces a high incidence of complete remission (CR) in patients with APL and is now established as a first-line therapy. However, ATRA resistance has become a clinical problem. Patients who relapsed after ATRA-induced CR have had difficulty in obtaining a second CR with ATRA therapy. Although several mechanisms have been postulated, treatment strategies to overcome resistance have not been established. We used a new synthetic retinoid, Am-80, as reinduction therapy for APL relapse after from ATRA-induced CR. Am-80 was several times more potent than ATRA in inducing differentiation in vitro. At a 6 mg/m2 dose, there were 24 evaluable patients; 14 (58%) achieved CR between days 20 and 58 (median, 37 days). Clinical response correlated with the in vitro response to Am-80. Adverse effects included retinoic acid syndrome (n = 1), hyperleukocytosis (n = 1), xerosis (n = 9), cheilitis (n = 8), hypertriglyceridemia (n = 16), and hypercholesterolemia (n = 15). Am-80 is active in APL after relapse from ATRA-induced CR. Further clinical trials are needed to establish strategies to overcome ATRA resistance.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Benzoates; Biomarkers, Tumor; Cheilitis; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Pilot Projects; Recurrence; Remission Induction; Salvage Therapy; Tetrahydronaphthalenes; Treatment Outcome; Tretinoin; Tumor Cells, Cultured

A phase I trial of all-trans-retinoic acid (ATRA) was conducted to establish the maximum tolerable dose (MTD) of ATRA given once daily to patients with solid tumors. Cancer patients for whom no standard therapy was available were treated with ATRA once daily. Doses were escalated in cohorts of at least three patients. The pharmacokinetics of ATRA were assessed on day 1 for all patients and weekly for 31 patients who received doses of > or = 110 mg/m2 per day. Patients were followed for toxicity and response. Correlations of toxicity frequency and grade with pharmacokinetic parameters were sought. In addition, correlation of changes in ATRA pharmacokinetics with the concentration of ATRA metabolites in plasma were sought. A total of 49 patients received ATRA at doses ranging from 45 to 309 mg/m2 per day. Hypertriglyceridemia was dose-limiting at 269 mg/m2 per day. Other frequent toxicities included mucocutaneous dryness and headache. With chronic dosing, plasma ATRA concentrations fell in 59% of patients. Stable, low, or variable [ATRA] were seen in 16%, 6%, and 16% of patients respectively. Age, gender, smoking, or concurrent medication did not correlate with the pharmacokinetic pattern. Severe toxicities tended to occur with initial peak [ATRA] of > or = 0.5 microgram/ml (1.7 microM), and the toxicity frequency did not change if [ATRA] decreased with continued dosing. No consistent change in 4-oxo-ATRA or retinoid glucuronide concentrations was observed with decreases in plasma [ATRA]. The recommended once-daily ATRA dose is 215 mg/m2, although significant interpatient variability is observed in toxicity and plasma retinoid concentrations. Although not statistically significant, more frequent and severe toxicity tended to occur in patients with higher plasma peak ATRA concentrations. Other factors, such as responses at target tissues, may be at least as important as the plasma ATRA concentration in predicting toxicity and/or response.

Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Hypertriglyceridemia; Male; Middle Aged; Neoplasms; Tretinoin

Patients with newly diagnosed acute promyelocytic leukemia (APL) are often obese or overweight, accompanied by metabolic disorders, such as dyslipidemia. However, the link between dyslipidemia and leukemia is obscure. Here, we conducted a retrospective study containing 1,412 cases (319 newly diagnosed APL patients, 393 newly diagnosed non-APL acute myeloid leukemia patients, and 700 non-tumor controls) and found that APL patients had higher triglyceride levels than non- APL and control groups. Using clinical data, we revealed that hypertriglyceridemia served as a risk factor for early death in APL patients, and there was a positive correlation between triglyceride levels and leukocyte counts. RNA sequencing analysis of APL patients having high or normal triglyceride levels highlighted the contribution of peroxisome proliferatoractivated receptor-α (PPARα), a crucial regulator of cell metabolism and a transcription factor involved in cancer development. The genome-wide chromatin occupancy of PPARα revealed that PPARα co-existed with PML/RARα within the super-enhancer regions to promote cell proliferation. PPARα knockdown affected the expression of target genes responsible for APL proliferation, including FLT3, and functionally inhibited the proliferation of APL cells. Moreover, in vivo results in mice having high fat diet-induced high triglyceride levels supported the connection between high triglyceride levels and the leukemic burden, as well as the involvement of PPARα-mediated-FLT3 activation in the proliferation of APL cells. Our findings shed light on the association between APL proliferation and high triglyceride levels and provide a genetic link to PPARα-mediated hyperlipidemia in APL.

Topics: Animals; Hyperlipidemias; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Mice; Oncogene Proteins, Fusion; PPAR alpha; Retrospective Studies; Tretinoin; Triglycerides

Topics: Acute Disease; Antineoplastic Agents; Humans; Hypertriglyceridemia; Pancreatitis; Tretinoin

Topics: Antineoplastic Agents; Cell Line, Tumor; Hepatocytes; Humans; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Tretinoin; Triglycerides

Topics: Acute Disease; Adolescent; Antineoplastic Agents; Female; Humans; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Pancreatitis; Tretinoin

All-trans-retinoic acid (ATRA) has been successfully used in the treatment of acute promyelocytic leukemia (APL). One of its adverse effects is acute pancreatitis. In the literature, a proposed cause of acute pancreatitis is hypertriglyceridemia. Here, we present the case of a 45-year-old male with APL, treated with ATRA combined with induction chemotherapy (cytarabine and idarubicin), who developed acute pancreatitis without overt hypertriglyceridemia. This finding suggests that hypertriglyceridemia might not be the sole contributing factor in the pathogenesis of ATRA-induced acute pancreatitis and that attention should be paid to the possibility that ATRA treatment causes acute pancreatitis in the absence of overt hypertriglyceridemia.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Humans; Hypertriglyceridemia; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Pancreatitis; Tretinoin

Previous research with an animal model of retinoid-induced hypertriglyceridemia, rats fed a 13-cis retinoic acid-containing diet in which casein was the dietary protein, has demonstrated that replacement of dietary casein with soy protein isolate can reduce the severity of this condition. A depressant action of soy protein vs. that of casein on serum triglyceride concentration has also been demonstrated in rats fed purified diets without supplemental retinoid. Because this action of soy protein appears to be due to its having a higher arginine-to-lysine ratio than casein, a study was done to determine how feeding a casein-containing diet supplemented with sufficient arginine, to give a dietary arginine-to-lysine ratio equivalent to that of soy protein, would affect the development of retinoid-induced hypertriglyceridemia. Groups of five-week-old male Fischer 344 rats (n = 7/group) were fed a control diet containing casein or one of three 13-cis retinoic acid-containing diets in which dietary nitrogen was provided as casein, casein + arginine, or soy protein. Incorporation of dietary 13-cis retinoic acid resulted in hypertriglyceridemia, with serum triglyceride concentrations of 2.00 and 7.23 mmol/l, or 177 and 640 mg/dl, for groups fed the control and casein + 13-cis retinoic acid diets, respectively. For animals fed the 13-cis retinoic acid-containing diets, serum triglyceride levels for the casein + arginine and soy protein diet groups (4.75 and 2.92 mmol/l, or 421 and 258 mg/dl, respectively) were significantly lower than for the casein group (p < 0.05); however, the value was significantly lower for the group fed the soy protein diet than for the group fed the casein + arginine diet. Serum and dietary arginine-to-lysine ratios were highly correlated (r = 0.93, p < 0.0001). Thus, supplementing dietary casein with arginine reduced the severity of retinoid-induced hypertriglyceridemia, but not as effectively as replacing casein with soy protein.

Topics: Amino Acids; Animals; Antineoplastic Agents; Arginine; Hypertriglyceridemia; Keratolytic Agents; Lipids; Male; Models, Animal; Proteins; Rats; Rats, Inbred F344; Tretinoin; Triglycerides

Topics: Antineoplastic Combined Chemotherapy Protocols; Cerebellum; Cerebral Infarction; Female; Humans; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Middle Aged; Tretinoin

Topics: Acute Disease; Adult; Female; Humans; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Pancreatitis; Tretinoin