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© 2002 American Society for Clinical Oncology Initial Clinical Trial of Oral TAC-101, a Novel Retinoic Acid Receptor-Alpha Selective Retinoid, in Patients With Advanced CancerByFrom the Developmental Therapeutics Program, Lombardi Cancer Center, Georgetown University Medical Center, and Washington Hospital Center, Washington, DC; Department of Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, University of Texas, Houston, TX; West Virginia University Health Science Center, Morgantown, WV; and Inveresk Research, Research Triangle Park, NC. Address reprint requests to Naiyer Rizvi, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; email: rizvin{at}mskcc.org
PURPOSE: The goals of this study were to determine the safety, toxicity, and pharmacokinetics of TAC-101, a novel synthetic retinoic acid receptor-alpha (RAR-  ) selective retinoid, in patients with advanced cancer. PATIENTS AND METHODS: Twenty-nine patients at two centers received oral TAC-101 at doses ranging from 12 to 34 mg/m2/d. Pharmacokinetic sampling was performed on days 1 and 28. RESULTS: The most frequent toxicities were myalgia/arthralgia, fatigue, and triglyceridemia. No dose-limiting toxicities were observed within the first 28 days up to 28 mg/m2. However, seven of 21 patients experienced venous thromboembolic events (VTEs) during TAC-101 treatment. Eight additional patients who received 34 mg/m2 were treated after a hypercoagulable work-up to exclude potential risk factors for VTE, and two of eight patients subsequently experienced VTEs. The maximum tolerated dose was exceeded at 34 mg/m2/d within the first 28 days, with one grade 3 hypertriglyceridemia, two grade 3 myalgia/arthralgia, and one grade 3 fatigue. One patient with advanced non–small-cell lung cancer had a complete response. No other responses were observed. No autoinduction of metabolism was observed with dosing over 28 days.
CONCLUSION: This is the first human clinical study with TAC-101, a RAR-
RETINOIDS, INCLUDING vitamin A and its analogs, regulate the morphogenesis, development, growth, and differentiation of cells.1 Retinoids and their precursors suppress carcinogenesis in experimental animals2 and have shown promise as chemopreventive agents in epithelial tumors3,4 and as therapeutic agents in acute promyelocytic leukemia.5 Retinoids function as ligands for two classes of nuclear hormone receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs).6 There are six known retinoid receptor subtypes, RAR-alpha, -beta, and -gamma and RXR-alpha, -beta, and -gamma. RXR forms heterodimers with RAR, vitamin D3 receptor, thyroid hormone receptor and other corticosteroid hormone receptors, and with certain orphan receptors for which no physiologic ligand has been identified. RARs and RXRs are expressed in most cells, and the effects of retinoic acid on cellular differentiation and death may reflect selective activation of RARs, RXRs, or both. Naturally occurring and synthetic ligands have been described that have distinctive binding properties and transactivation effects on the various RAR and RXR subtypes, thereby allowing differential modulation of retinoid receptor gene expression.7 All-trans-retinoic acid binds to RAR with high affinity but does not bind to RXR, whereas 9-cis-retinoic acid binds to both RARs and RXRs.8
TAC-101 (4-[3,5-bis (trimethylsilyl) benzamide] benzoic acid)9 is a synthetic retinoid with selective binding affinity for RAR-
The pharmacokinetics and distribution of TAC-101 have been studied in mice, dogs, and monkeys. The oral formulation of TAC-101 demonstrates good bioavailability in mice and dogs (62% to 94%). It is primarily excreted in the bile and has minimal urinary excretion. TAC-101 does not accumulate in the blood over time, and plasma concentrations of TAC-101 do not decrease after chronic administration. The starting dose for the phase I human study was based on data from repeat-dose toxicity studies. In the rodent, TAC-101 markedly decreased serum vitamin A levels and produced testicular atrophy at 0.4 mg/kg (2.4 mg/m2), and the effective antineoplastic dose was 8 mg/kg (24 to 48 mg/m2). Data from a preliminary 13-week pilot study in monkeys demonstrated that TAC-101 produced testicular atrophy at This phase I clinical study of TAC-101 was conducted to determine the safety, toxicity, and pharmacokinetics of this agent in patients with advanced cancer.
Patient Selection Inclusion criteria for the study included patients who (1) had histologically confirmed advanced cancer that was resistant or refractory to standard therapy or for which no standard therapy exists, or had inoperable or incompletely resected cancer of the lung or head and neck, and who had received definitive radiation therapy to residual disease; (2) were 18 to 80 years of age; (3) had an Eastern Cooperative Oncology Group performance status of 0 to 2; (4) had adequate hematologic, hepatic, and renal function; and (5) had a negative pregnancy test and used effective means of contraception. Exclusion criteria included patients who (1) had chemotherapy, immunotherapy, radiotherapy or investigational therapy within 4 weeks of the study; (2) had brain metastases (unless treated and clinically stable); or (3) had previous treatment with other retinoids. All patients provided signed informed consent, and the clinical protocols were approved by the Georgetown University and M.D. Anderson Cancer Center institutional review boards.
Treatment Plan Standard laboratory tests, which included complete blood counts, chemistry survey, coagulation tests, lipid profiles, thyroid tests, and urinalysis, were performed serially during the study. Imaging studies to evaluate possible tumor response were performed as clinically indicated during the study. The two sites, M.D. Anderson and Georgetown, conducted their trials as parallel phase I investigations with protocols differing only in the dose escalation schemes.
Dosage Schedule, Definition of Dose-Limiting Toxicities, and Dose Modification At M.D. Anderson Cancer Center, the starting dose was also 12 mg/m2 and the dose was doubled until drug-related grade 1 toxicity was observed in any patient, and thereafter the dose was escalated by 50% for subsequent dose levels. If grade 2 toxicity was observed, the dose was escalated by 25% for subsequent dose levels. When a DLT was observed in one patient, an additional three patients were entered at that dose level. If only one of the six total patients experienced a DLT, dose escalation was allowed to continue. However, if two or more of the six patients experienced a DLT, then the maximum tolerated dose was exceeded and three additional patients were treated at the dose level below DLT. DLT in this study was defined as grade 3 toxicities (common toxicity criteria) with the exception of grade 2 cardiac ischemia or pericardial disease, grade 2 weight gain/loss, grade 2 elevation in prothrombin time or partial thromboplastin time, or decrease in fibrinogen, and grade 2 neurologic change, vision change, or seizure occurring within the first 4-week study period. The rationale for defining the above grade 2 toxicities as DLT was based on rodent data. In rat studies, the adverse effects at the 1.5-mg/kg dose level included decreases in serum protein and increases in prothrombin time and partial thromboplastin time. At the 24-mg/kg dose level of TAC-101, death occurred in rats as early as 5 weeks, and weight loss, abnormal gait, ataxia, and bone fractures preceded deaths by at least 2 weeks. In the current, parallel, phase I study, if a patient developed a DLT, the treatment was discontinued until the toxicity level returned to baseline, at which time TAC-101 was restarted at 50% of the dose at which the DLT was observed. If the DLT occurred at the 50% dose, the drug was discontinued and the patient was removed from the study.
Pharmacokinetic Studies Samples were analyzed for parent TAC-101 plasma concentration by a validated gas chromatography–mass spectrometry technique. After the addition of internal standard (Am55S, Taiho Pharmaceutical; final concentration 100 ng/mL), 0.2 mL of 0.5 M KH2P04 and 2 mL of methyl-t-butyl ether were added to each 0.2-mL plasma sample. The mixture was rotated for 10 minutes at room temperature, then centrifuged. The ether extracts were evaporated to dryness (Turbovap LV; Zymark, Hopkinton, MA), and then the derivatization mixture (50 µL of acetonitrile, 10 µL of pentafluorobenzyl bromide, and 10 µL of triethylamine) was added. The sample was subsequently incubated at room temperature for 30 minutes. Hexane (0.5 mL) and water (0.15 mL) were added to the derivatized samples. Next, the samples were rotated for 10 minutes and then centrifuged. The hexane extract was evaporated to dryness, and the samples were then reconstituted with 0.1 mL ethyl acetate and loaded into autoinjector vials. Analyte separation was achieved by gas chromatography (Varian 3400; Varian Chromatography Systems, Palo Alto, CA), and quantitation was achieved by mass spectrometry (Finnigan SSQ7000 Quadrapole; Finnigan). The system utilized a DB-5MS capillary column (15 m x 0.25 mm; J&W Scientific) with a temperature gradient from 230°C to 311°C at 12°C/min. The injector volume was 2 µL with a 1:9 split ratio, and helium was used as the carrier gas. The mass spectrometer used a negative chemical ionization mode monitoring the [M-CH2C6F5]- ions at m/z 384 for both TAC-101 and Am55S. Chromatographic retention times were 5.5 minutes for Am55S and 5.7 minutes for TAC-101 with baseline resolution between peaks. No chromatographic peaks suggestive of metabolic products were observed in patient sample analyses. Utilization of a quadratic calibration curve over the plasma TAC-101 concentration range of 1 ng/mL (lower limit of quantitation) to 500 ng/mL yielded control data that were within -3.5% to 5.0% of the mean theoretical values. Assay accuracy was within 6.2%, whereas the within-day precision values were 2% to 7% and between-day precision values were 0% to 5% across all quality-control concentrations. At least two thirds of duplicate high-, intermediate-, and low-concentration standards were required to be within 15% of theoretical concentrations for acceptance of an analytic run. Pharmacokinetic assessments were conducted by the standard two-stage approach by use of noncompartmental techniques for each patient plasma TAC-101 data set (WinNonlin version 1.1, Scientific Consulting, Apex, NC). The predicted drug accumulation index (R) was estimated in each patient by the equation
where K is the terminal elimination rate and tau is the dosing interval. These data were compared with the observed accumulation index as represented by the ratio of the area under the concentration-time curve (AUC) on day 28 to the AUC on day 1.
Analysis of variance was used to test the linear relationship of normalized day 1 AUCinf (ie, AUCinf/dose level) versus dose level and normalized day 1 maximum concentration (Cmax) (ie, Cmax/dose level) versus dose level in the noncompartmental model. All tests were two-sided with a significance level of alpha
Methods and Materials for the Thrombophilia Screening Assays Analysis of whole blood by polymerase chain reaction (PCR) for the presence of the MTHFR mutation was performed by amplifying a highly conserved 198-base pair sequence of cellular DNA by primer pair MTHFR1/MTHFR2 with subsequent digestion with restriction enzyme HinfI. The amplified products (amplicons) were detected and visualized after electrophoresis on agarose gels and stained with ethidium bromide. The absence of C-677-T mutation was considered negative; C-677-T mutation present in one allele of the MTHFR gene was heterozygote; and C-677-T mutation present in both alleles of the MTHFR gene was homozygote. The presence of factor V Leiden mutation by PCR was performed by amplifying a highly conserved 267-base pair sequence of cellular DNA by primer pair PR-6967/PR-990 with subsequent digestion with restriction enzyme MnL1. The amplified products (amplicons) were detected and visualized after electrophoresis on agarose gels and stained with ethidium bromide. The absence of 1691 G/A mutation was considered negative; the presence of 1691 G/A mutation in one allele of the factor V Leiden gene was heterozygote; and the presence of 1691 G/A mutation in both alleles of the factor V Leiden gene was homozygote. Both of these tests (MTHFR and factor V Leiden) were developed by, and had their performance characteristics determined by, the Molecular Diagnostics Laboratory, Georgetown University Hospital.
Patient Characteristics and Dose Levels Studied A total of 29 patients were treated with TAC-101 at six dose levels. Eighteen patients were enrolled at M.D. Anderson Cancer Center, and 11 patients were enrolled at Georgetown University. The starting dose for this study was 12 mg/m2/d, and three patients were enrolled at each center at this dose level. At Georgetown University, the dose was doubled for subsequent cohorts of patients until drug-related toxicity one grade below the DLT occurred in any of the patients at that dose level, and thereafter the dose was escalated by 40% increments. At M.D. Anderson Cancer Center, the dose was doubled until drug-related grade 1 toxicity was observed in any patient, and thereafter the dose was escalated by 50%. If grade 2 toxicity was observed, subsequent dose escalation was restricted to 25%. Twenty men and nine women were entered onto study, and they ranged in age from 35 to 76 years. The tumor types of patients who entered onto study included bronchogenic carcinoma (n = 15), head and neck carcinoma (n = 6), sarcoma (n = 3), prostate cancer (n = 2), and one patient each with colorectal cancer, thymoma, and pleural mesothelioma. Patient characteristics are listed in Table 1.
Adverse Events The toxicities experienced by three or more of the 29 patients at any time in this study that were felt to be "possibly," "probably," or "definitely" related to TAC-101 are listed in Table 2. In general, treatment-related toxicities were typical of those reported in the literature for other retinoids. Data are shown for the worst toxicity grade that a patient experienced at any time while enrolled onto the study. The DLT for dose escalation decision points was defined as a DLT that occurred during the first 28 days of treatment. The dose escalation schema and the DLT observed by study site are illustrated in Fig 1.
Skin changes (eg, dry skin, erythema, exfoliation) were common and occurred in 90% of the patients, but skin changes never reached DLT levels. Headache was mild in 12 patients and moderate in one patient. The most common constitutional toxicities were myalgia/arthralgia (59% of patients) and fatigue (55% of patients). Within the first 28 days at the highest dose level (34 mg/m2/d), one patient experienced grade 3 fatigue, one had grade 3 myalgia, and two had grade 3 arthralgia/myalgia. The musculoskeletal symptoms were variable from patient to patient. The myalgias and arthralgias were symmetric, typically involved multiple areas, and tended to favor the lower extremities. There was no arthritis or joint swelling observed in association with the myalgias and arthralgias. Typically, nonsteroidal anti-inflammatory drugs were not successful in ameliorating the musculoskeletal toxicity, and narcotics were used in a small number of patients with only partial success. With continuous dosing, grade 3 fatigue was also observed in an additional two patients beyond 28 days at the 18-mg/m2 and 24-mg/m2 dose levels. The fatigue seemed to be more than would have been expected in this patient population. In particular, worsening of fatigue symptoms with continued dosing beyond 28 days was observed in the absence of progressive disease, suggesting a study-drug relationship. Additionally in some cases, resolution or improvement of fatigue was observed when the TAC-101 was discontinued. Triglyceride elevation was observed in 27 of the 29 patients and was dose related. All of the 11 patients at the highest dose level (34 mg/m2) experienced hypertriglyceridemia (Fig 2). Elevations were often observed within the first 1 to 2 weeks of the beginning of TAC-101 therapy. Although grade 3 hypertriglyceridemia was observed within the first 28 days of treatment in only one out of 29 patients at the 34-mg/m2 dose level, grade 3 hypertriglyceridemia was observed with continuous dosing beyond 28 days in five out of 29 patients at doses of 24 mg/m2 and above. In all cases, triglyceride elevations were reversible on temporary or permanent discontinuation of TAC-101, and no cases of clinical pancreatitis were observed.
Hepatic transaminase elevations were frequently observed at the grade 1 level. Two patients (7%) out of 28 had ALT increases at the grade 2 level. There was no dose-limiting hepatotoxicity observed with TAC-101 administration. A total of 22 of 29 patients had an elevation in total lactate dehydrogenase (LDH) levels of 50% or more above baseline values. Eighteen of these 22 patients had baseline LDH values within the normal range. The elevations in LDH were quite consistent between patients, ranging from 1.51 to 2.54 times the baseline values (mean ± SD, 1.85 ± 0.28). There were no discernible alterations in serum vitamin A, luteinizing hormone, follicle-stimulating hormone, or testosterone concentrations in either men or women with TAC-101 treatment (data not shown).
Thrombotic Risk and Evaluation
The study was amended to reduce potential hypercoagulable risk factors in participating subjects by prescreening otherwise eligible cancer patients for past or family history of thrombosis and by performing a comprehensive thrombophilia panel for congenital and acquired disorders. The protocol amendments stipulated that patients were not allowed on study if any mutations were detected for factor V Leiden or prothrombin, or if homozygous mutations were detected for methylene tetrahydrofolate reductase. Additionally, the study was amended so that patients underwent baseline lower extremity duplex Doppler ultrasound examinations and pulmonary ventilation/perfusion lung scans to rule out the presence of occult VTE. At the time that the study amendments were proposed, three patients had been accrued at the 34-mg/m2 dose level without evidence of DLT within the first 4 weeks. However, enrollment onto this dose level was expanded to further evaluate the possible toxicities, particularly the potential for VTE. Twenty-three patients were screened after the amendments became effective. Six out of 23 patients were excluded from study entry because of positive PCR mutation findings, and nine patients did not go on study for other reasons. Eight patients were enrolled at the 34-mg/m2 dose level, and two out of eight patients developed VTE despite the exclusion of patients thought to have an increased potential for hypercoagulability. Markers of hypercoagulability were monitored longitudinally (baseline and weeks 4, 6, and 8) in eight patients receiving TAC-101. The mean levels (n = 8) of antithrombin III, protein C, and protein S activities seemed to remain essentially stable for the first month of TAC-101 administration. Between weeks 4 to 8, no changes occurred in the mean levels of antithrombin III (n = 3) and protein S (n = 3) activities, but there was a substantial increase in mean protein C activity (n = 3) from 133.54% (± 9.63%) at 4 weeks to 178.20% (±55.02%) at 8 weeks. Mean TFPI levels increased markedly within the first month of TAC-101 administration from 117.71 ± 33.00 ng/mL (n = 8) to 199.93 ± 80.35 ng/mL (n = 8). All of the individual levels of TFPI reverted back toward baseline as soon as TAC-101 was discontinued, whether the patient had received the medication for 4 or 8 weeks. Mean plasminogen activator inhibitor type 1 levels remained stable throughout the medication period (n = 8 at baseline and at week 4; n = 5 at week 6; n = 3 at week 8) but seemed to decrease slightly in the small number of individuals observed after TAC-101 was discontinued. Mean levels of tissue plasminogen activator essentially were unchanged throughout the study. There was a progressive increase in the proportion of patients whose D-dimer assay results became positive with continued TAC-101 administration (week 4, five of seven positive; week 6, three of five positive; week 8, three of three positive). Prothrombin fragment 1.2 (PF1.2) and TAT also were measured. The mean baseline levels of these two markers (n = 8) were elevated above the normal range and rose substantially over the first 4 weeks of TAC-101 administration (n = 8). The 3 patients who remained on TAC-101 through week 8 continued to have elevated mean values of these markers, with progressive increase in TAT and essentially stable PF1.2 levels.
Responses
There was a suggestion of disease stabilization induced by TAC-101 (Table 4). Of the 29 patients enrolled onto the study, four patients received treatment with TAC-101 for more than 3 months, and three patients received treatment with TAC-101 for more than 6 months. Of these seven patients, four patients were discontinued from the study for reasons other than progressive disease, as described in Table 4.
Pharmacokinetics Pharmacokinetic parameters were assessable in 32 doses of TAC-101 given to 23 patients. Twelve of those patients had assessable parameters on both dose 1 and dose 28. Time of maximal concentration (Tmax) typically occurred between 3 and 4 hours after dose administration. The mean terminal half-life was 6.4 hours for day 1 and 7.8 hours for day 28. Similarly, the mean apparent volumes of distribution were 26 and 35 L/m2, respectively. The mean apparent clearance was 3 L/h/m2 on both assessment days and varied over a relatively small range (three-fold) with coefficients of variation from 28% to 32%. Nonnormalized TAC-101 apparent clearance was only weakly associated with either patient body-surface area or weight. Dose 1 AUC and Cmax values seemed to increase in a dose-linear fashion for the range studied (Figs 4 and 5) and no evidence of nonlinearity in drug clearance was found on statistical assessment (P values 0.86 and 0.54 for AUC and Cmax, respectively). Comparison of day 1 to day 28 disposition did not reveal any consistent pattern of accumulation or reduction in concentrations (Fig 6). These data were corroborated by similarities in the predicted versus actual accumulation indices. In addition, a paired t test demonstrated no difference between day 1 and day 28 AUC (P = .857). Inspection of the AUC and Cmax values for the cohort of seven patients who experienced venous thromboembolic problems failed to reveal any meaningful differences when compared with the group of patients without such symptoms.
TAC-101 is a unique RAR- selective retinoid that has been shown preclinically to inhibit AP-1 activity and angiogenesis. TAC-101 has been shown in murine studies to inhibit hepatic metastasis and prolong survival with a number of tumor xenografts.10-15 Based on the preclinical data with TAC-101, this phase I study was conducted as a dose-finding study to determine the safety, toxicity, and pharmacokinetics of this agent in patients with advanced cancer.
The most frequently observed toxicities were hypertriglyceridemia, fatigue, and joint-related pain symptoms. Skin reactions (cheilitis, xeroderma, skin peeling) were relatively infrequent and were milder with TAC-101 than with previously observed classical retinoids. Ocular toxicity (eye dryness, conjunctivitis) was not encountered with TAC-101. These mucocutaneous toxicities are a frequent complication of RAR-selective retinoids and pan-receptor agonists, but these toxicities are minimal with RXR-selective retinoids such as LGD1069, and they are observed only at the higher dose levels.16-19 It has been proposed that RAR- The most frequently occurring DLT was hypertriglyceridemia. Only one patient within the first 28 days experienced grade 3 hypertriglyceridemia (34-mg/m2 dose level). However, a total of five out of 29 patients experienced grade 3 hypertriglyceridemia (two patients at 24-mg/m2 and three patients at 34-mg/m2 dose levels) with continuous dosing beyond 28 days. Of all the clinical toxicities observed in this study, only hypertriglyceridemia was clearly dose related. Given the dose-proportional elevation of triglycerides and the observation of only one out of six DLT at the 24-mg/m2 dose level, the recommended phase II dose is 24 mg/m2 with this treatment schedule. However, the frequency of venous thromboembolism, which was probably in excess of the expected rate in cancer patients, and the temporal relationship between TAC-101 and VTEs would suggest a hypercoagulable potential induced by the administration of TAC-101 (nine of 29 patients, 31%). The small number of patients that were studied prospectively for alterations in coagulation precluded establishing a cause-effect relationship between TAC-101 and VTE; however, the mean increases in D-dimers, PF1.2, and TAT are suggestive of such a relationship. The pattern of sustained AUC and stable systemic clearance during continual dosing that was found in this initial human study of TAC-101 differs from that of all-trans-retinoic acid or 9-cis-retinoic acid.17,21 The latter two drugs seem to upregulate their own metabolism, resulting in dramatic reductions in AUC with continuous dosing. These observations also suggest a difference between TAC-101 and previously described retinoids. One patient with recurrent non–small-cell lung cancer had a complete response to treatment with TAC-101, and his response has been maintained since study drug discontinuation. This clinical complete response is unique because in previous phase I and II solid-tumor studies, traditional retinoids have not demonstrated a cytotoxic-like effect.
Although TAC-101 was originally synthesized as a selective RAR-
In summary, TAC-101 is an interesting and unique retinoid that targets RAR-
Supported in part by Taiho Pharmaceutical Co, Ltd, Tokyo, Japan.
W.K.H. is a consultant for Taiho Pharmaceutical.
1. Chambon P: The retinoid signaling pathway: Molecular and genetic analyses. Semin Cell Biol 5: 115-125, 1994[CrossRef][Medline] 2. Lotan R: Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells. Biochim Biophys Acta 605: 33-91, 1980[Medline] 3. Hong WK, Endicott J, Itri LM, et al: 13-cis-Retinoic acid in the treatment of oral leukoplakia. N Engl J Med 315: 1501-1505, 1986[Abstract] 4. Hong WK, Lippman SM, Itri LM, et al: Prevention of second primary tumors with isotretinoin in squamous cell carcinoma of the head and neck. N Engl J Med 323: 795-801, 1990[Abstract]
5. Warrell RP Jr, de The H, Wang ZY, et al: Acute promyelocytic leukemia. N Engl J Med 329: 177-189, 1993 6. Mangelsdorf DJ, Umesono K, Evans RM: The retinoid receptors, in Sporn MB, Roberts AB, Goodman DS (eds): The Retinoids, ed 2. New York, NY, Raven Press, 1994, pp 319-349 7. Chambon P: A decade of molecular biology of retinoic acid receptors. FASEB J 10: 940-954, 1996[Abstract] 8. Heyman RA, Mangelsdorf DJ, Dyck JA, et al: 9-cis-Retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68: 397-406, 1992[CrossRef][Medline] 9. Yamakawa T, Kagechika H, Kawachi E, et al: Retinobenzoic acids: 5—Retinoidal activities of compounds having a trimethylsilyl or trimethylgermyl group(s) in human promyelocytic leukemia cells HL-60. J Med Chem 33: 1430-1437, 1990[CrossRef][Medline]
10. Sun SY, Yue P, Dawson MI, et al: Differential effects of synthetic nuclear retinoid receptor-selective retinoids on the growth of human non–small cell lung carcinoma cells. Cancer Res 57: 4931-4939, 1997 11. Sakukawa R, Murakami K, Ikeda T, et al: Effect of 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101) on the liver metastasis of colon 26-L5 carcinoma cells. Oncol Res 10: 287-293, 1998[Medline] 12. Murakami K, Wierzba K, Sano M, et al: TAC-101, a benzoic acid derivative, inhibits liver metastasis of human gastrointestinal cancer and prolongs the life-span. Clin Exp Metastasis 16: 323-331, 1998[CrossRef][Medline] 13. Shibata J, Murakami K, Wierzba K, et al: Anticancer effect of 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101) against A549 non–small cell lung cancer cell line is related to its anti-invasive activity. Anticancer Res 20: 3169-3176, 2000[Medline] 14. Shibata J, Murakami K, Aoyagi Y, et al: The induction of apoptosis and inhibition of AP-1 activity by TAC-101 (4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid) may result in life prolonging effect in animals bearing metastasizing cancer. Anticancer Res 20: 3583-3590, 2000[Medline]
15. Murakami K, Sakukawa R, Sano M, et al: Inhibition of angiogenesis and intrahepatic growth of colon cancer by TAC-101. Clin Cancer Res 5: 2304-2310, 1999 16. Band PR, Besner JG, Leclaire R, et al: Phase I study of 13-cis-retinoic acid toxicity. Cancer Treat Rep 66: 1759-1761, 1982[Medline]
17. Lee JS, Newman RA, Lippman SM, et al: Phase I evaluation of all-trans-retinoic acid in adults with solid tumors. J Clin Oncol 11: 959-966, 1993
18. Miller VA, Benedetti FM, Rigas JR, et al: Initial clinical trial of a selective retinoid X receptor ligand, LGD1069. J Clin Oncol 15: 790-795, 1997
19. Rizvi NA, Marshall JL, Dahut W, et al: A phase I study of LGD1069 in adults with advanced cancer. Clin Cancer Res 5: 1658-1664, 1998 20. Standeven AM, Teng M, Chandraratna RA: Lack of involvement of retinoic acid receptor alpha in retinoid-induced skin irritation in hairless mice. Toxicol Lett 22: 231-240, 1997 21. Rizvi NA, Marshall JL, Ness E, et al: Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer. Clin Cancer Res 4: 1437-1442, 1998[Abstract]
22. Wu Q, Dawson MI, Zheng Y, et al: Inhibition of trans-retinoic acid–resistant human breast cancer cell growth by retinoid X receptor-selective retinoids. Mol Cell Biol 17: 6598-6608, 1997
23. Shalinsky DR, Bischoff ED, Lamph WW, et al: A novel retinoic acid receptor-selective retinoid, ALRT1550, has potent antitumor activity against human oral squamous carcinoma xenografts in nude mice. Cancer Res 57: 162-168, 1997
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26. Sun SY, Yue P, Hong WK, et al: Augmentation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by the synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) through up-regulation of TRAIL receptors in human lung cancer cells. Cancer Res 60: 7149-7155, 2000 Submitted February 23, 2001; accepted May 14, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1 mg/kg (12 mg/m2), produced clinical pathologic changes of hypertriglyceridemia and increase in alkaline phosphatase at 
0.05. 
, the major retinoic acid receptor subtype in skin, mediates retinoid-induced skin irritation. Recent data would also support the hypothesis that RAR-
