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PubMed2002

Missing expression of pRb2/p130 in human retinoblastomas is associated with reduced apoptosis and lesser differentiation.

PURPOSE: Although the retinoblastoma gene (RB/p105) has been intensely investigated as a prototype suppressor gene in humans, mutational data on the Rb family member pRb2/p130 (p130) has only recently been reported. A protective role against apoptosis has been suggested for pRb/p105, both in vitro and in vivo. However, only limited information is available on the role of pRb2/p130 in controlling apoptosis. The purpose of this study was to determine the extent of a role of this gene in the neoplasms that give the Rb family its name. METHODS: Forty-two human retinoblastomas were retrospectively examined by immunohistochemical labeling of the Rb-related proteins and the results compared with cellular kinetic characteristics: the apoptotic index (AI) and the mitotic index (MI). RESULTS: The retinoblastomas that did not express p130 showed a significantly lower AI than those that expressed p130. This result was also supported by flow cytometry on a human Saos-2 cell line that was transiently transfected with RB2/p130. The p130(-) tumors displayed a lesser degree of differentiation than the p130(+) ones. CONCLUSIONS: These observations give evidence that expression of p130 is inversely correlated with higher rates of apoptosis in human retinoblastomas and give an additional example of this regulator's role in cellular differentiation.

Apoptosis↗
PubMedDate not supplied

Retinoblastoma in Taiwan: survival rate and prognostic factors.

PURPOSE: The mortality rate of patients with retinoblastoma still varies in developing countries, and data for Asia and Taiwan are relatively scarce. In this retrospective study, we aimed to describe the survival characteristics and prognostic factors of 54 retinoblastoma cases diagnosed at the Taipei Veterans General Hospital between 1982 and 2004. METHODS: From medical records, we retrospectively analyzed the data of 54 consecutive children diagnosed in our hospital between 1982 and 2004 as having retinoblastoma. Data on sex, laterality, age at diagnosis, presenting signs, family history, duration of symptoms, lag time for treatment, spread of tumor, treatment mode, and survival time were collected. RESULTS: Seventy-five percent of the cases were unilateral and 25% of the cases were bilateral. The mean patient age at the time of diagnosis was 26.3 months. The mean duration of symptoms was 2.96 months. After diagnosis, the mean lag time before treatment was 2.59 months. The most common presenting signs were leukocoria (71.4%), red, painful, or tearing eye (18.4%), strabismus (14.3%), and blurred vision (14.3%). Only 3 of 52 cases (5.8%) were familial. The most common sites of extraocular invasion included the central nervous system (seven cases) and the orbit (seven cases). In 13.7% of the cases, parents had refused the treatment suggested by the doctors. None of the patients developed a secondary neoplasm. The 5-year overall survival rate was 80.9% (unilateral, 88.1%; bilateral, 64.3%). The survival rate of patients with an interval between onset and treatment of <5 months was 90.9%, and that for an interval of >5 months was 60.9%. The survival rate of those with a lag time of <2.5 months was 90.0%, and that of those with one of >2.5 months was 31.3%. The survival rate of patients with intraocular and extraocular disease was 96.9% and 39.2%, respectively. Extraocular disease was an independent factor indicating a poor prognosis, determined by multivariate analysis. CONCLUSIONS: The mortality rate of patients with retinoblastoma is higher in Taiwan than in developed countries. The proportion of patients' parents refusing or delaying treatment in Taiwan is high. The factors for a poor prognosis were an interval between onset and treatment of >5 months, a lag time before treatment of >2.5 months, and extraocular disease. The duration of symptoms was not a prognostic factor. The only independent factor indicating a poor prognosis was extraocular disease.

Age Distribution↗
PubMed2004

Branch retinal artery occlusion: a complication of iron-deficiency anemia in a young adult with a rectal carcinoid.

We report a case of branch retinal artery occlusion (BRAO) in a patient with iron-deficiency anemia. Various ophthalmological and laboratory studies were performed. A 32-year-old man had a sudden decrease of vision in his left eye to counting fingers at 30 cm two days ago. The left fundus showed a cherry-red spot and milky-white edema, except for the upper temporal region of the macula, and an optic disc malformation. Fluorescein angiography revealed leakage from the disc and a slightly delayed filling time in the left eye but an arterial filling defect was not noted. The differential diagnosis in this young patient includes polycythemia, hypercoagulopathy, coagulation abnormalities, trauma, hypertension, and autoimmune diseases such as systemic lupus erythematosus. Laboratory examinations revealed no abnormalities except for iron-deficiency anemia. The patient was treated with stellate ganglion block, hyperbaric oxygen, and ferrous sulfate. His visual acuity never recovered to better than 0.08. He had a coincidental rectal carcinoid and the tumor was excised surgically. No metastasis was observed. BRAO can be a complication of anemic retinopathy and can lead to severe visual loss without early medication.

Adult↗
PubMed1984

Evaluating the usefulness in neuro-ophthalmology of visual field examinations peripheral to 30 degrees.

The value of the information obtained from Goldmann manual kinetic perimetry beyond 30 degrees was examined. Of 229 randomly selected patients in a University eye clinic who had visual fields performed for reasons other than glaucoma or ocular hypertension only 3 patients had abnormalities confined to the PVF of one or both eyes. In none of these three patients was the PVF necessary to detect disease (Graves' disease, 2 cases; retinoschisis, 1 case). The PVF was useful in determining the localization of the disorder and/or the therapeutic management in 14 patients of whom 4 of these had retinitis pigmentosa and 5 had other disorders where the PVF showed the extent of the retinal damage. For ergo-ophthalmologic purposes the PVF was useful in 45 patients; most frequently because the extent of abnormality provided a basis for warning the patient. In some cases the PVF was considered to be useful for economic disability determination or to exclude significant PVF defects in a patient with only one visually useful eye. In 77 patients the PVF of each eye was abnormal but not of ergo-ophthalmologic significance. If these data can be extrapolated to automated static perimetry, there will be a very great incremental cost for any clinically useful information obtained from the examination of the PVF. Because the cost-effectiveness of the examination must be compared with competing methods of obtaining information, it is proposed that the PVF be examined (1) whenever indicated for ergo-ophthalmologic reasons, or (2) when the CVF examination does not resolve a clinical problem for which there is a reasonably high probability that (a) additional clinically useful information will be obtained by examination of the PVF after the results of the CVF examination have been analyzed, or (b) the eye is likely to have a condition that can be detected or followed best by PVF examination.

Adenoma↗
PubMed1998

Optic nerve breast metastasis mimicking meningioma.

PURPOSE: We report on an optic nerve breast metastasis masquerading initially as a central retinal vein occlusion and later as an optic nerve meningioma. METHODS: A 60-year-old female presented with a left central retinal vein occlusion (CRVO). She represented 7 months later with left upper ptosis, proptosis and painful rubeotic glaucoma Computed tomography (CT) and magnetic resonance imaging suggested an optic nerve meningioma. On referral to the regional orbital unit a mild left external ophthalmoplegia was noted and, in view of previous right mastectomy and chemotherapy 3 years earlier, the left optic nerve was biopsied simultaneously with left enucleation of her painful eye. RESULTS: Histopathology showed infiltration of the optic nerve and meningeal sheath spreading into the subretinal space and vitreous by malignant epithelial cells, consistent with breast origin. Further CT imaging and bone scans revealed no other metastases. Single field left orbit radiotherapy of 20 Gy was given in five fractions and Arimidex (Zeneca Pharmaceuticals, Cheshire, England) was commenced with the cessation of tamoxifen. The patient was also given an ocular prosthesis. Sadly, she lost vision in her other eye due to retrograde malignant invasion of her optic chiasm and died 6 weeks later. CONCLUSIONS: Orbital and choroidal metastases are relatively common but isolated optic nerve metastases are extremely rare. Progressive infiltration of the nerve is likely to enhance CRVO ischaemia and resultant rubeotic glaucoma. In the diagnosis of CRVO, proptosis or external ophthalmoplegia, the presence of pre-existing malignant disease should raise concerns, as delay in diagnosis may affect outcome, particularly if the metastases are sensitive to pharmacological therapy.

Blepharoptosis↗
PubMed1999

A possible selective impairment of magnocellular function in compression of the anterior visual pathways.

Two parallel visual systems, the magnocellular (M) and parvocellular (P) pathways, originate from different types of retinal ganglion cells, and are known to be segregated in different portions of the pregeniculate visual pathways. Their relative contribution to two main cortical streams, dorsal and ventral, is still under discussion, but it is reasonable to suppose that selective damage to the M or P subcortical system might interfere with specific aspects of processing within one or the other cortical system. Using two different apparent-motion tasks, we compared the performance of patients affected by compression of the ventral part of the pregeniculate visual pathways with that of normal controls. In the first task, observers detected small displacements of a low-contrast vertical bar, while in the second task they estimated the visible persistence of moving dots. In the first task, patients were impaired with parafoveal displays, especially in the temporal portion of the visual field. In the second task, patients showed reduced suppression of visible persistence at long, but not at short, exposure durations. Three considerations support the hypothesis that these results represent a selective impairment of the M system. First, M axons are more likely to suffer from compression, particularly in the case of a mass growing from below since they are known to occupy a ventral subpial position in the optic chiasm and tract. Second, the performance of patients with a ventral compression is consistent with the characteristics of the response properties of P ganglion cells, which have previously been shown to exhibit elevated and unmodulated thresholds for displacement detection in the macaque monkey. Third, such patients are less sensitive to the inhibitory signals that suppress visible persistence, which probably originate in the M system.

Adenoma↗
PubMed1998

The outcome of chemoreduction treatment in patients with Reese-Ellsworth group V retinoblastoma.

OBJECTIVE: To determine the outcome of chemoreduction treatment in patients with Reese-Ellsworth group V retinoblastoma. METHODS: Prospective analysis of 27 eyes in 22 patients with group V retinoblastoma treated with either 2- or 6-cycle chemoreduction and focal treatment methods (argon laser photocoagulation, transpupillary thermotherapy, cryotherapy, and plaque radiotherapy). The need for external beam irradiation and the eventual globe salvage rate were assessed. Median follow-up was 28 months. RESULTS: There were 16 eyes in the 2-cycle chemoreduction treatment group and 11 eyes in the 6-cycle chemoreduction treatment group. No significant difference was noted between the 2 groups with respect to baseline patient and eye findings. After chemoreduction treatment, external beam irradiation was necessary in 12 (75%) of 16 eyes in the 2-cycle chemoreduction treatment group and in 4 (36%) of 11 eyes in the 6-cycle chemoreduction treatment group. There was no statistical difference between the 2- and 6-cycle chemoreduction treatment groups with respect to necessity for external beam irradiation (logistic regression analysis). All 4 eyes in the 2-cycle chemoreduction treatment group and 3 of 12 eyes in the 2-cycle chemoreduction treatment and irradiation group were eventually enucleated, the globe salvage rates being 0% and 75%, respectively. Two of 7 eyes in the 6-cycle chemoreduction treatment group and 1 of 4 eyes in the 6-cycle chemoreduction treatment and irradiation group were enucleated, the globe salvage rates being 71% and 75%, respectively. Except for the 2-cycle chemoreduction treatment group, in which the globe salvage rate was significantly lower (P = .03), there was no difference among the other 3 groups (2-cycle chemoreduction treatment and irradiation, 6-cycle chemoreduction treatment, and 6-cycle chemoreduction treatment and irradiation) with respect to globe salvage (logistic regression analysis). CONCLUSIONS: Local tumor control of group V retinoblastoma is possible with 6-cycle chemoreduction and focal therapy when external beam irradiation is not used. A larger sample size is necessary to determine how often external beam irradiation can be avoided.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Cataract surgery and intraocular lens implantation in patients with retinoblastoma.

OBJECTIVE: To report the visual outcome and complications after extracapsular cataract extraction with posterior chamber intraocular lens (IOL) implantation in eyes that underwent external beam radiotherapy for the treatment of retinoblastoma. METHODS: Eleven eyes of 8 patients aged 1.5 to 8.0 years at the time of surgery for irradiation-induced cataract were observed for 6 to 39 months (mean [+/-SD], 20+/-10 months). A standard technique of extracapsular cataract extraction, posterior chamber IOL implantation, pars plana posterior capsulotomy, and pars plana anterior vitrectomy was performed in 9 eyes, and secondary IOL placement was performed in 2 eyes. RESULTS: All eyes that underwent primary IOL implantation achieved visual acuities equal to or better than those best ever recorded prior to the development of the cataract. There were no postoperative complications, and all eyes experienced minimal postoperative inflammation. The 2 eyes that underwent secondary IOL implantation achieved their best-corrected aphakic visual acuities but experienced a prolonged course of postoperative inflammation. CONCLUSION: Intraocular lens placement in the posterior chamber of eyes with regressed retinoblastoma and irradiation-induced cataract seems to be a safe and effective method for the correction of aphakia.

Cataract↗
PubMed1998

Clinicopathologic features of retinoblastoma after primary chemoreduction.

BACKGROUND: Primary chemotherapy is a new treatment approach in retinoblastoma, aiming to avoid radiogenic adverse effects, such as second tumor-associated mortality, as observed following external beam irradiation. OBJECTIVE: To describe the clinical and histopathologic regression pattern after primary chemotherapy in retinoblastoma. METHODS: Five patients with sporadic bilateral retinoblastoma underwent planned enucleation of their functionally blind eye after 2, 3 (in 2 patients), 4, and 6 courses of primary chemotherapy with carboplatin, etoposide, cyclophosphamide, and vincristine. The eyes were examined histopathologically, using light microscopy and immunohistochemical analysis with proliferation markers. RESULTS: One patient had a type 1 (cottage cheese) regression and 4 patients had either a type 2 (fish flesh) or a type 3 (combined) regression pattern. Histopathologic examination revealed a complete tumor necrosis in 1 patient with type 1 regression after 3 courses of chemotherapy and in 1 patient with type 3 regression after 4 courses of chemotherapy. The remaining 3 patients with type 2 or type 3 regression had histologically still active proliferative tumor cells after 2, 3, and 6 courses of chemotherapy. CONCLUSION: This article correlates histopathologically the clinically described efficacy of primary chemotherapy in the treatment of retinoblastoma, underlining, however, the necessity of careful observation and the use of ancillary treatment whenever there is no complete tumor regression.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation.

OBJECTIVES: To examine the epidemiologic and clinical characteristics of the ocular manifestations of von Hippel-Lindau (VHL) disease and to detect phenotype-genotype relationships of disease severity. DESIGN: A cross-sectional clinical and molecular genetic study. PATIENTS AND METHODS: One hundred eighty-three affected VHL gene carriers from 81 unrelated pedigrees were interviewed and examined; clinical data were also obtained from 12 living and 39 deceased affected relatives. DNA extracted from venous blood was used to identify mutations in the VHL gene. RESULTS: The prevalence of ocular angiomatosis (hemangioblastomas) in von Hippel-Lindau disease was 67.8% (124/183), and the mean number of angiomas in gene carriers was 1.85 (range, 0-15). Neither prevalence nor angioma count increased with age. Severe vision loss in 1 or both eyes was associated with presentation at a young age. The cumulative probability of incurring vision loss by age 50 years was 35% in all gene carriers, 55% in those with angiomatosis, and significantly worse in those coming to us with symptoms. Angiomas were nonrandomly distributed in the fundus, occurring rarely at the posterior pole (1% of retinal tumors) and commonly on the optic disc (8% of eyes) and supratemporal retina. Complications of ocular angiomatosis included disc and retinal neovascularization; secondary angioma formation; retinal detachment, exudation, and membrane; and retinal and vitreous hemorrhage. Germ-line VHL mutations were detected in 161 of 183 patients and 69 (85%) of 81 pedigrees and included deletions (n= 16), missense (mutations causing amino acid substitutions; n = 24), nonsense (premature stop codons; n = 15), frameshift (n = 13), and splice-site (n = 1) mutations. There was no association between the type or position of mutation and the severity of ocular angiomatosis. CONCLUSIONS: A systematic clinical description of a large cohort of VHL gene carriers further defines the ocular phenotype. There is no general influence of germline mutation on severity of ocular disease in VHL. CLINICAL RELEVANCE: The ophthalmic and molecular genetic description of patients with VHL disease.

Adolescent↗
PubMed1999

VHL gene deletion and enhanced VEGF gene expression detected in the stromal cells of retinal angioma.

OBJECTIVE: Retinal angioma frequently occurs in von Hippel-Lindau (VHL) disease. However, VHL gene alterations have not been documented in retinal angiomas. METHODS: Using tissue microdissection and polymerase chain reaction amplification, we have analyzed 7 retinal angiomas associated with VHL disease for loss of heterozygosity of the VHL gene. In addition, vascular endothelial growth factor expression was evaluated in these tumors by immunohistochemistry and in situ hybridization. RESULTS: All 6 informative retinal angiomas showed loss of heterozygosity of the VHL gene. Loss of heterozygosity was detected in vacuolated "stromal" cells, but not in vascular cells or reactive glial tissue. Vascular endothelial growth factor protein and messenger RNA were also present in vacuolated "stromal" cells. CONCLUSIONS: These findings suggest that vacuolated "stromal" cells represent the true neoplastic component in retinal angioma. These cells express vascular endothelial growth factor and therefore may be responsible for abundant neovascularization of retinal angioma.

Adult↗
PubMed1999

External beam radiotherapy in retinoblastoma: tumor control and comparison of 2 techniques.

OBJECTIVE: To investigate eye conservation, local control, and complication rates among children with retinoblastoma treated with 2 different external beam radiotherapy (EBR) techniques. METHODS: Fifty-eight eyes in 42 patients received EBR as the primary treatment modality for retinoblastoma (median follow-up, 37 months). The EBR technique was relative lens-sparing (RLS) in 26 eyes and modified lateral beam (MLB) in 32 eyes. Both groups were comparable in Reese-Ellsworth retinoblastoma classification. If necessary, patients received focal salvage therapy. RESULTS: At 24 months, eye conservation rates were 88.5% and 89.1% among eyes treated with RLS and MLB, respectively (P = .40); tumor control rates without salvage therapy were 84.6% and 53.3% (P = .02), respectively. Among eyes with Reese-Ellsworth stage IV and V disease, eye conservation rates were 88%+/-8% and 83%+/-9% at 36 months in the RLS and MLB groups, respectively, and local tumor control rates were 81%+/-10% and 51%+/-12%. Percentages of eyes without cataract at 36 months were 83.1% and 63.0%, respectively (P = .40). Among patients observed for at least 18 months, midfacial hypoplasia developed in 38.5% and 29.4%, respectively (P = .70). CONCLUSIONS: The EBR technique was associated with high eye conservation and local control rates. Salvage therapy was performed significantly less frequently in the RLS group compared with the MLB group, and complication rates in both groups were similar.

Child, Preschool↗
PubMed2000

Subconjunctival carboplatin in retinoblastoma: impact of tumor burden and dose schedule.

OBJECTIVE: To evaluate the impact of tumor burden and chemotherapy dose scheduling on the response to subconjunctival carboplatin treatment in a murine transgenic retinoblastoma model. METHODS: Eighty simian virus 40 T antigen-positive mice were treated at age 5 or 10 weeks. Six control animals received placebo treatment. Twenty-four 5-week-old mice received 6 subconjunctival carboplatin injections at doses of 30 to 300 microg delivered at 72-hour intervals. Fifty 10-week-old mice received either 6 or 12 subconjunctival carboplatin injections at doses of 30 to 300 microg delivered at 72-hour intervals. All eyes were obtained at age 16 weeks for histopathologic examination. Eyes were graded as positive if any tumor was present. RESULTS: All simian virus 40 T antigen-positive control eyes contained large tumor foci throughout the retina. Subconjunctival carboplatin injections controlled tumors in a dose-dependent manner. Tumor control was observed in 50% of treated eyes at 138.3 microg for the 10-week-old 6-injection group, 94.3 microg for the 5-week-old 6-injection group, and 85.9 microg for the 10-week-old 12-injection group. CONCLUSION: Increased tumor burden requires an increase in subconjunctival carboplatin dose scheduling to maintain local tumor control in this murine model of retinoblastoma. CLINICAL RELEVANCE: This study documents the efficacy of subconjunctival carboplatin in the treatment of an animal model of retinoblastoma. These data establish a framework for further human clinical trials. Arch Ophthalmol. 2000;118:1549-1554

Animals↗
PubMed2001

Molecular basis of low-penetrance retinoblastoma.

Retinoblastoma is a malignant tumor of the retina that occurs primarily in young children as a result of mutations in the retinoblastoma gene (RB), the first tumor suppressor gene to be identified. In about 35% to 40% of patients with retinoblastoma, an RB gene mutation is present in the germline, resulting in hereditary transmission of the disease. Most families with hereditary retinoblastoma demonstrate autosomal dominant inheritance with almost complete penetrance and high expressivity. However, some families display an inheritance pattern characterized by reduced penetrance and expressivity. Recent advances in our understanding of the structure and function of the retinoblastoma protein (pRB) now provide new insights into the molecular basis of this low-penetrance form of retinoblastoma. Low-penetrance retinoblastoma mutations either cause a reduction in the amount of normal pRB that is produced (class 1 mutations) or result in a partially functional mutant pRB (class 2 mutations).

Genes, Retinoblastoma↗
PubMed2001

Pediatric enucleation: analysis of volume replacement.

OBJECTIVES: To determine the percent volume replacement by an implant and prosthesis, the long-term sequelae of poor volume replacement, and specific guidelines for volume replacement in pediatric patients. METHODS: A retrospective observational study of 16 pediatric patients who underwent enucleation (group 1) and 31 adult patients enucleated in childhood (group 2) was performed. The total volume replacement and the volume replacement by the implant were determined. The incidence of secondary surgical procedures for superior sulcus deformity, enophthalmos, ptosis, ectropion, and socket contraction was determined. RESULTS: The average percent volume replaced by the implants in group 1 patients was 68%. The average percent volume replaced by the implants in group 2 patients was 21%. Seventy-one percent of patients in group 2 underwent secondary implant surgery to augment volume and eliminate superior sulcus deformity and enophthalmos. CONCLUSIONS: The placement of an adequately sized implant in pediatric patients may obviate the need for secondary augmentation of socket volume in adulthood. The authors suggest an implant 2 mm less in diameter than the axial length of the eye in pediatric patients.

Adolescent↗
PubMed2002

Hyperfractionated external beam radiation therapy in the treatment of murine transgenic retinoblastoma.

OBJECTIVE: To determine the in vivo efficacy of hyperfractionated external beam radiation therapy (EBRT) in comparison with standard daily EBRT in a murine model of heritable retinoblastoma. METHODS: Two hundred twenty eyes from 6-week-old simian virus-40 large T-antigen--positive mice were treated with a total dose of EBRT ranging from 10-76 Gy (1000 to 7600 rad). One hundred ten eyes underwent EBRT administered in 2.0-Gy (200-rad) fractions once per day. Forty-two eyes received hyperfractionated EBRT administered in 1.2-Gy (120-rad) fractions twice per day, while 48 eyes received EBRT twice daily in fractions of 5.0 Gy (500 rad). Twenty eyes served as untreated controls. All eyes were obtained for histopathologic examination and graded positive if any tumor was present. RESULTS: A dose-dependent inhibition of ocular tumor was observed for EBRT in these transgenic retinoblastoma mice. The tumor control dose for 50% of eyes (TCD(50)) treated with 2.0 Gy fractions of EBRT was 45 Gy (4500 rad) when treatments were administered once daily. A significant increase in tumor control was observed when treatments were administered twice per day at fractions of 1.2 Gy, resulting in a TCD(50) of 33 Gy (3300 rad) (P =.003). A further increase in tumor control was observed when twice-daily EBRT was administered in 5.0 Gy fractions resulting in a TCD(50) of 28 Gy (2800 rad). CONCLUSIONS: Hyperfractionated EBRT safely and effectively controls intraocular retinoblastoma in this transgenic animal model. Use of hyperfractionation allows for a reduction in total radiation delivered dose, while shortening the total treatment time. CLINICAL RELEVANCE: This treatment approach may be applicable in the management of pediatric retinoblastoma by maintaining excellent tumor control, while reducing treatment-associated complications.

Animals↗
PubMed2002

Toxicity and dose-response studies of 1alpha-hydroxyvitamin D2 in a retinoblastoma xenograft model.

BACKGROUND: Although calcitriol (1,25-dihydroxycholecalciferol) and vitamin D(2) inhibit retinoblastoma growth in the athymic (nude) mouse xenograft (Y-79 cell line) model of retinoblastoma, they can cause severe toxicity. OBJECTIVE: To examine the toxicity of and dose-dependent response for the inhibition of tumor growth for 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)), an analogue with reduced systemic toxicity, in the athymic Y-79 mouse model. METHODS: Mice were randomized into treatment and control groups for 5-week toxicity and dose-response studies. Treatment was via oral gavage 5 times per week. Dose-response studies measured tumor inhibition and drug serum levels. Tumor size and body weight were measured weekly together with various criteria for toxicity. Animals were euthanized at the end of the treatment period. Tumors and kidneys were harvested, and serum was analyzed for calcium and drug levels. RESULTS: Doses of 0.1 to 1.2 microg/d were selected on the basis of toxicity studies for the dose-response trial. Tumor weight and volume in the 0.2-microg and 0.3-microg doses were significantly lower than in controls. Mortality rates and kidney calcification in mice treated with doses of 0.1 to 0.3 microg were lower than those observed in studies of calcitriol and vitamin D(2). CONCLUSION: A vitamin D analogue, 1alpha-OH-D(2), inhibits tumor growth in this xenograft model of retinoblastoma with less toxicity than calcitriol and vitamin D(2).

Animals↗