isotretinoin and Neoplasm-Metastasis

Metastatic renal cell carcinoma remains one of the most treatment-resistant malignancies in humans. As such, long-term survival is limited to a minority of patients. Interferon-alpha and interleukin-2 induced major responses in some patients with renal cell carcinoma, and in so doing generated a great deal of interest and hope. However, clinical benefit is limited to relatively few patients. Here, we briefly discuss the management of metastatic renal cell carcinoma, and then elaborate on several novel treatment approaches in development, including retinoids, monoclonal antibodies, and antiangiogenesis strategies.

Topics: Adjuvants, Immunologic; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Combined Modality Therapy; Humans; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Neoplasm Metastasis; Prognosis; Retinoids

Topics: Aged; Aged, 80 and over; Aminolevulinic Acid; Antineoplastic Agents; Bowen's Disease; Carcinoma; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Evaluation Studies as Topic; Female; Humans; Interferon-alpha; Interferons; Isotretinoin; Keratolytic Agents; Male; Neoplasm Metastasis; Photochemotherapy; Photosensitizing Agents; Retinoids; Skin Neoplasms

To test the hypothesis that modulation of Bcl-2 with 13-cis retinoic acid (CRA)/interferon-alpha2b (IFN) with paclitaxel (TAX), or mitoxantrone, estramustine and vinorelbine (MEV) will have clinical activity in men with metastatic castrate-resistant prostate cancer (CRPC).. 70 patients were treated with either MEV (Arm A) in a 3-week cycle or CRA/IFN/TAX with an 8-week cycle (Arm B). Patients were assessed for response, toxicity, quality of life (QOL), and the effect of treatment on Bcl-2 levels in peripheral blood mononuclear cells (PBMC).. The PSA response rates were 50% and 23%, measurable disease response rates (CR+PR) 14% and 15%, and median overall survival 19.4 months and 13.9 months on Arm A and Arm B respectively. Transient grade 4 neutropenia occurred in 18 and 2 patients, and grade 3 to 4 thrombosis in 7 patients and 1 patient in Arm A and Arm B respectively. Patients on Arm B reported a clinically significant decline in QOL between baseline and week 9/10 (.71 s.d.), and a significantly lower level of QOL than Arm A (p = 0.01). As hypothesized, Bcl-2 levels decreased with CRA/IFN therapy only in Arm B (p = 0.03).. Treatment with MEV was well tolerated and demonstrated clinical activity in patients with CRPC. Given the adverse effect of CRA/IFN/TAX on QOL, the study of other novel agents that target Bcl-2 family proteins is warranted. The feasibility of measuring Bcl-2 protein in a cooperative group setting is hypothesis generating and supports further study as a marker for Bcl-2 targeted therapy.. CDR0000067865.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Interferons; Isotretinoin; Male; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Paclitaxel; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Quality of Life; Survival Rate; Teratogens; Treatment Outcome; Vinblastine; Vinorelbine

Radio-iodine is effective in treating metastatic differentiated thyroid cancers. In 20% of cases, however, these tumours fail to take up radio-iodine, and treatment options are then limited. Failure of iodine uptake might be reversible using redifferentiating agents. Retinoids redifferentiate a variety of cell types and increase iodine uptake in thyroid tumour cells in vitro. The aim of this study was to assess whether oral isotretinoin could increase radio-iodine uptake in patients with iodine-uptake-negative metastatic thyroid cancer.. Patients who had iodine-uptake-negative metastatic papillary or follicular thyroid cancers were selected from the thyroid database at The Royal Marsden Hospital and enrolled to an open-label, non-randomised phase II trial. Sites of metastatic disease were assessed using computed tomography or magnetic resonance imaging, and absence of iodine uptake was confirmed using a diagnostic radio-iodine scan before study entry. In eligible patients, isotretinoin was prescribed at 1.5 mg/kg/day orally for 8 weeks. Response was assessed within 2 weeks of completing treatment with repeat radio-iodine scan. All patients were reviewed every 2 weeks during treatment for assessment of toxicity.. Sixteen patients were treated with isotretinoin between January 2001 and July 2002: nine with metastatic papillary thyroid cancer, five with metastatic follicular cancer and two with Hurthle cell carcinoma. Median age was 57 years. All patients tolerated 8 weeks of oral isotretinoin. Mucocutaneous side-effects and minor changes in biochemical or lipid profiles were documented in most patients. In one patient, radio-iodine uptake increased after retinoid administration; however, this was not large enough to permit a significant dose of iodine to be given to sites of metastatic disease. In the other 15 patients, no radio-iodine uptake was documented.. Treatment with isotretinoin does not reliably increase radio-iodine uptake in patients with metastatic thyroid cancer. This treatment alone does not enable radio-iodine to be used for further treatment.

Topics: Adenocarcinoma, Follicular; Administration, Oral; Adult; Aged; Carcinoma, Papillary; Combined Modality Therapy; Female; Humans; Iodine Radioisotopes; Isotretinoin; Male; Middle Aged; Neoplasm Metastasis; Thyroid Neoplasms

We conducted a prospective quality-of-life analysis during outpatient immunotherapy in 22 patients with progressive metastatic renal cell carcinoma (RCC) treated with subcutaneous interferon-alpha2a and subcutaneous interleukin-2. Patients' quality of life was assessed by the European Organization for Research and Treatment of Cancer quality-of-life questionnaire QLQ-C30 before (week 0) and once during immunotherapy (week 3). Advanced renal cancer patients completed a total of 30 questionnaires before therapy (week 0) and after 3 weeks of therapy. Their mean quality of life (global-quality-of-health status) deteriorated significantly, from 64 to 41 (P

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Health Status; Humans; Injections, Subcutaneous; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Outpatients; Prognosis; Quality of Life; Treatment Outcome

After aggressive surgery and chemotherapy, patients (PTS) with advanced solid tumors have often an impaired immune function that may facilitate tumor relapse. We have demonstrated, in a phase IB study, that administering low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA), there was a significant improvement of the immune function, with low toxicity, in PTS with advanced tumors that had been treated with aggressive surgery and chemotherapy (Clin Cancer Res 7: 1251-1257, 2001). A further A phase II study (International J Oncology 20: 1275-82, 2002) showed the efficacy of IL-2/RA in improving immunological parameters and in prolonging response in the same category of PTS. Aim of this study was evaluate the clinical and laboratory outcome of 214 patients, with advanced solid tumors, that, after aggressive surgery and chemotherapy, were treated with: subcutaneous IL-2 1.8 x 10(6) IU and oral RA, 0.5 mg/Kg for 5 days/week for 2 cycles of 3 weeks, with a 1-week rest, for up to 2 years. After a median follow-up time of 31 months, there was a statistically significant improvement in the number of lymphocytes, T4/T8 ratio, NK, with respect to baseline values. Responses were maintained for a median time of 36.4 months, while median survival was not reached yet (57% of PTS alive). These data show that the administration of low-dose IL-2/RA determines, with a low toxicity, a sustained increase in the immunological parameters known to be prognostically relevant.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; C-Reactive Protein; Dose-Response Relationship, Drug; Female; Humans; Injections, Subcutaneous; Interleukin-2; Isotretinoin; Killer Cells, Natural; Lymphocytes; Male; Middle Aged; Neoplasm Metastasis; Rheumatoid Factor; Survival Analysis

The goal of the current report was to demonstrate the long-term efficacy of outpatient subcutaneous (sc) interferon alpha (IFN-alpha) and sc interleukin 2 (IL-2)-based combination regimens in patients with metastatic renal cell carcinoma.. In three consecutive clinical trials, 443 patients received combined sc IFN-alpha and sc IL-2 (n = 97 patients); combined sc IFN-alpha, sc IL-2, and intravenous (iv) 5-fluorouracil (5-FU) (n = 260 patients); or combined sc IFN-alpha, sc IL-2, and iv 5-FU with oral 13cis-retinoic acid (n = 86 patients).. The median overall survival was 21+ months. The 2-year, 5-year, and 13-year survival rates were calculated at 45.26%, 15.96%, and 8.96%, respectively. The median time to disease progression was 6 months. The 2-year, 5-year, and 13-year progression free survival rates were 17.84%, 9.54%, and 9.20%, respectively.. The current data suggest that combined outpatient sc IFN-alpha and sc IL-2, according to the Atzpodien regimen, achieves long-term survival benefits in a subset of patients with metastatic renal cell carcinoma, both with and without 13-cis-retinoic acid and/or 5-fluorouracil.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Outpatients; Recombinant Proteins; Survival Analysis

It is suggested that immunotherapy may have a better role than cytotoxic chemotherapy in the treatment of metastatic renal cell carcinoma.. A phase II study of alpha-interferon 2a (IFN2a) and 13-cis-retinoic acid (CRA) in the treatment of metastatic renal cell carcinoma.. Twenty-two patients with no previous systemic therapy were treated with IFN2a daily at 3 million units (MU) and escalated to 6 and 9 MU if tolerated, together with CRA given orally at 1 mg/kg per day in two divided doses. Changes in quality of life were also assessed.. Twenty patients were available for assessment. Three patients (14%) achieved a partial response and five patients (23%) had stable disease. No patient achieved a complete response. A durable response was observed in partial responders with median length of response of 44 weeks (range 32-59 weeks). Therapy was stopped in seven (35%) patients due to treatment-related toxicities, and quality of life was worsened in the majority of patients.. IFN2a and CRA has a low response rate and significant toxicity, and the combination as standard treatment of metastatic renal cell carcinoma is not recommended, despite the suggestion that CRA may lengthen the response to IFN2a.

Topics: Adult; Aged; Biopsy, Needle; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Recombinant Proteins; Survival Rate; Treatment Outcome

To evaluate the therapeutic effects and systemic toxicities of a capecitabine-based home therapy regimen in patients with metastatic renal cell carcinoma, 30 patients were enrolled in a phase II clinical trial. Treatment consisted of oral capecitabine combined with subcutaneous recombinant human interferon-alpha 2a, recombinant human interleukin-2 and oral 13-cis-retinoic acid. There were two (7%) complete responses (CRs) and eight (27%) partial remissions (PRs), for an overall objective response rate of 34% (95% CI 17-53%). Except one, all responses are ongoing, with a median duration of 9+ and 8+ months for CRs and PRs, respectively. Additionally, 12 patients (40%) reached stable disease. Eight patients (27%) showed continued disease progression despite treatment. Therapy was well tolerated and was given in the outpatient setting. Capecitabine-related World Health Organization (WHO) grade 2 and 3 toxicities were observed in five and two patients respectively, and were limited to fatigue, nausea/vomiting, diarrhoea, stomatitis, dermatitis and hand-and-foot syndrome. The substitution of capecitabine for 5-FU in the pre-existing biochemotherapy regimen did not result in a reduced therapeutic efficacy and showed significant anti-tumour activity in patients with advanced renal cell carcinoma.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Capecitabine; Carcinoma, Renal Cell; Deoxycytidine; Female; Fluorouracil; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Treatment Outcome

Twenty-five patients with metastatic malignant melanoma were treated with isotretinoin (13-cis-retinoic acid) orally at 1 mg/kg daily and recombinant interferon alfa-2a (INF-alpha) subcutaneously at 3 million units daily for 16-48 weeks. Therapy was well tolerated; fatigue and hyperlipidemia were the most frequent dose-limiting toxicity and necessitated dose reductions in 14 patients. Two patients achieved a complete response, and 3 responded partially for a total response rate of 20% (95% confidence interval: 4-36%). Responses occurred primarily in patients with limited tumor burden and disease confined to the skin and lymph nodes. Significant elevations in peripheral blood 2'-5'-oligoadenylate synthetase activity and natural killer activity were observed with therapy. The magnitude of these changes, however, was not predictive of response. Biopsy specimens of two responding lesions showed extensive necrosis of tumor. One specimen showed large aggregates of melanophages in association with tumor. The combination of isotretinoin and IFN-alpha is an active, easily administered regimen with acceptable toxicity for metastatic malignant melanoma.

Topics: 2',5'-Oligoadenylate Synthetase; Adult; Aged; Antineoplastic Agents; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Killer Cells, Natural; Lymph Nodes; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Necrosis; Neoplasm Metastasis; Neoplasm Staging; Recombinant Proteins; Skin Neoplasms

We conducted a phase I/II clinical trial evaluating the sequential outpatient combination of S.C. recombinant human interleukin-2 (rIL-2; given at 10 MIU/m2 b.i.d. on days 3-5 weeks 1 and 4 and at 5 MIU/m2 on days 1, 3, and 5 of weeks 2 and 3), s.c. recombinant human alpha-interferon (rIFN-alpha; given at 6 MIU/m2 on day 1 of weeks 1 and 4 and on days 1, 3, and 5 of weeks 2 and 3 and at 9 MIU/m2 on days 1, 3, and 5 of weeks 5-8), i.v. bolus 5-fluorouracil (5-FU; given at 1,000 mg/m2 once weekly during weeks 5-8), and i.v. bolus vinblastine (given at 6 mg/m2 once weekly during weeks 5 and 8) in conjunction with p.o. 13-cis-retinoic acid (13-C-RA; given at 35 mg/m2 daily during weeks 1-8). Therapy was always given in the outpatient setting. Grade 3 constitutional symptoms (malaise, chills, fevers, anorexia) were observed in 4%-8% of treatment cycles and required a 50% reduction in the doses of rIL-2 and rIFN-alpha. None of the patients experienced major 5-FU-related toxicities such as severe diarrhea and/or stomatitis; up to 20% of patients developed vinblastine-associated peripheral polyneuropathy, which was reversible after the cessation of therapy. 13-cis-Retinoic acid produced no significant side effect; no toxic death occurred. Among 24 patients with progressive metastatic disease, there were 4 complete remissions (lung, lymph nodes) and 6 partial remissions (lung, pleura, liver, lymph nodes, and peritoneal carcinosis), for an overall objective response rate of 42% (95% confidence interval, 22%-63%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Combined Modality Therapy; Female; Fluorouracil; Humans; Interferon Type I; Interleukin-2; Isotretinoin; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Remission Induction; Treatment Outcome; Vinblastine

To evaluate the effectiveness of isotretinoin for improving (131)I uptake in recurrent/metastasized thyroid cancer with no/insufficient (131)I uptake.. Retrospective analysis of 25 patients treated between June 1999 and May 2001.. 15 female and 10 male patients were given isotretinoin at 1 mg/kg for 3 months, followed by (131)I treatment. All patients received a (131)I scan 72 h after administration, thyroglobulin measurement, chest X-ray and ultrasound of the neck, and some patients underwent a (18)F-fluorodeoxyglucose (FDG) positron emission tomography (n=14) and computed tomography scan of the chest (n=11).. In two out of 14 patients with raised thyroglobulin but no (131)I uptake, a slightly improved (131)I uptake was seen. In a further 11 patients an improvement of (131)I uptake of known lesions was desired or further non-(131)I-accumulating lesions were known. A dosimetrically relevant improvement of uptake was seen in three of these patients. (18)F-FDG uptake and thyroglobulin did not correlate with the success/failure of the isotretinoin treatment. Side effects including a strong "sunburn", cheilitis, mucositis, conjunctivitis and raised transaminases occurred in two-thirds of patients. They were of an overall tolerable level and were reversible after isotretinoin had been stopped.. From our clinical experience over a period of 2 years we conclude that the therapeutic effect of isotretinoin in thyroid cancer is certainly less than previously reported. An indiscriminate use of isotretinoin in all patients with otherwise untreatable thyroid cancer cannot be recommended.

Topics: Adenocarcinoma, Follicular; Adult; Aged; Aged, 80 and over; Carcinoma, Papillary; Female; Fluorodeoxyglucose F18; Humans; Iodine Radioisotopes; Isotretinoin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies; Thyroid Neoplasms; Tomography, Emission-Computed; Treatment Outcome

The purpose of this study was to examine the effects of 13-cis-retinoic acid (13-cis-RA) on the growth regulation of DU-145 human prostatic cancer cells. The results of these experiments demonstrate that cell growth and metastatic potential of DU-145 cells were significantly inhibited by 13-cis-RA (10 microM). In order to elucidate the possible molecular mechanisms of 13-cis-RA action on prostate cancer cells, we examined the expression of nuclear receptor genes (hRXR alpha) and found that 13-cis-RA treated cells showed higher mRNA expression for hRXR alpha nuclear receptors compared to untreated cells. To elucidate further the possible biochemical mechanisms associated with these alterations, we analyzed the phosphorous metabolites by MR spectroscopy and found that the major metabolites were PME, (PC, PE) and DPDE (UDP-GalNAc, UDP-GLcNAc). The DU-145 cells and xenografts, which were both treated with 13-cis-RA, showed a two-fold decrease in DPDE's, compared to their controls. The higher resolution spectra of perfused cells revealed that phosphocholine levels were twice as high in 13-cis-RA-treated DU-145 cells as compared to untreated cells. These investigations demonstrate for the first time that 13-cis-RA inhibits the growth of human prostatic cancer cells, and this inhibition is associated with an increase in hRXR alpha nuclear receptor gene expression and alterations in phosphorous metabolites detected by 31P MR spectroscopy.

Topics: Animals; Cell Division; Collagen; Collagenases; Fibronectins; Gene Expression; Humans; Isotretinoin; Laminin; Magnetic Resonance Spectroscopy; Male; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Prostatic Neoplasms; Receptors, Retinoic Acid; Tumor Cells, Cultured

Murine squamous carcinoma cells (KLN205) grown in a medium supplemented with the retinoid, 13-cis retinoic acid (RA), had dose-dependent, selective increases in the expression of certain lectin receptors, which correlated with a dramatic decrease in the ability to form pulmonary colonies (P = .0003) (Couch MJ, Pauli BU, Weinstein RS, Coon JS: JNCI, 78:971-977, 1987). These findings suggest a possible relationship between the RA-induced glycoconjugate alterations and the decreased experimental metastatic behavior. We further define the mechanism of RA's action. The finding that RA treatment (5 X 10(-6) M, 5 X 10(-7) M) did not perturb the cell cycle of KLN205 cells provides further proof that the decreased metastatic behavior is not attributable to any inhibition in the rate of growth or to alterations in the cell cycle. Furthermore, since stable subpopulations with variable lectin binding could not be detected, the mechanism of RA's action does not appear to be due to selection of variant tumor-cell subpopulations. Finally, in a series of experiments designed to determine the reversibility of the RA treatment, the RA-induced decrease in metastatic behavior reverted back to a more metastatic state in the same time frame (3 days) as the reversion of the RA-induced changes in cell-surface glycoconjugate expression. This reversion provides further evidence for a close relationship between the RA-induced modulation of tumor cell-surface glycoconjugate expression and the decreased metastatic behavior; it suggests that transient, reversible modulation of the tumor cell surface may play a role in determining metastatic behavior.

Topics: Animals; Carcinoma, Squamous Cell; Cell Cycle; Flow Cytometry; Glycoconjugates; Isotretinoin; Lectins; Lung Neoplasms; Male; Mice; Neoplasm Metastasis; Receptors, Mitogen; Tretinoin; Tumor Cells, Cultured

KLN 205 murine squamous carcinoma cells were grown in medium supplemented with the retinoid 13-cis-retinoic acid (RA) to study the relationship between RA-induced cell surface changes and alterations of the metastatic phenotype. Modulation of the cell surface glycoconjugate expression was measured by flow cytometric analysis of the RA-treated tumor cells stained with fluoresceinated lectins. RA treatment (5 X 10(-6) and 5 X 10(-7) M) altered the glycoconjugate expression of KLN 205 cells in a selective, dose-dependent fashion. Tumor cells grown in RA-supplemented medium for more than 4 days demonstrated greatly increased binding of fluoresceinated Griffonia simplicifolia I lectin, peanut lectin, wheat-germ lectin, concanavalin A, and soybean lectin (P less than .001), but the increased binding of Ulex europaeus lectin was of a much smaller magnitude (P = .02). After 15 days of growth in these noncytotoxic or cytostatic concentrations of RA, malignant KLN 205 cells had a greatly decreased proclivity to metastasize, as measured by the lung colony assay (P = .0003). The RA-induced cell surface glycoconjugate changes preceded the decrease in experimental metastatic potential. Since enzymatic (neuraminidase) alteration of the tumor cell surface to produce glycoconjugate expression similar to that seen in RA-treated cells also reduced the ability of the KLN 205 cells to form lung colonies (P = .0022), it is suggested that RA-induced alteration of the cell surface carbohydrate antigens is related to the decreased experimental metastatic potential seen in tumor cells treated with RA.

Topics: Animals; Antigens, Neoplasm; Carbohydrates; Cell Division; Dose-Response Relationship, Drug; Fluorescence; Isotretinoin; Killer Cells, Natural; Lung Neoplasms; Mannose; Mice; Neoplasm Metastasis; Phenotype; Time Factors; Tretinoin

The effects of retinol, all-trans-retinoic acid, isotretinoin and etretinate on the activity of basement membrane collagen degrading enzyme was studied in melanoma cells. The results indicated that retinoids at concentrations of up to 10(-6) M did not significantly affect type IV collagenolytic activity in these cells in vitro. Since type IV collagenolytic enzyme may be involved in the metastatic potential of tumour cells, it appears that retinoids do not affect the metastatic potential of melanoma cells by affecting type IV collagenolytic activity.

Topics: Cells, Cultured; Etretinate; Humans; Isotretinoin; Melanoma; Microbial Collagenase; Neoplasm Metastasis; Retinoids; Skin Neoplasms; Tretinoin; Vitamin A

The possible effect of oral 13 cis retinoic acid (13-cis-RA) on the carcinogenic process induced by 28 weekly s.c. injections of 1,2-dimethylhydrazine (DMH) in 34 Wistar rats was investigated. Using immunohistology, precancerous and cancerous stages were compared with the same stages induced by DMH without additional 13-cis-RA in 33 rats. M1 antigens, which characterize modifications in goblet-cell differentiation occurring early in rat colonic carcinogenesis, were used to investigate the possible effect of retinoids on differentiation during precancerous stages. From 3-20 weeks after the start of the experiment, no significant differences were observed in the timing of M1 antigens in the 2 groups of rats. It was also observed that 13-cis-RA had no effect on histological lesions associated with precancerous mucosa, nor on the occurrence of intestinal adenocarcinomas. Thus, under these conditions, oral administration of 13-cis-RA did not significantly inhibit precancerous or cancerous stages of intestinal carcinoma development.

Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Animals; Carcinogens; Colonic Neoplasms; Dimethylhydrazines; Female; Intestinal Neoplasms; Isotretinoin; Methylhydrazines; Neoplasm Metastasis; Neoplasms, Experimental; Precancerous Conditions; Rats; Rats, Inbred Strains; Tretinoin

Studies have suggested that both natural and synthetic retinoids have extensive chemopreventive activity against a variety of carcinogens in vivo and in vitro. We have previously shown that growth of human breast cancer cells can be inhibited by retinoids, and retinoic acid-binding proteins have been demonstrated in these cell lines and tumor biopsies. We studied the activity of 13-cis-retinoic acid in the treatment of 18 patients with advanced breast cancer refractory to standard cytotoxic and/or endocrine therapy. Patients began on 0.5 mg/kg and escalated to 8 mg/kg over a one-month period unless toxicity (dry skin, dry mucosa, cheilitis, conjunctivitis) forced dose reduction. All these toxicities responded promptly to dose reduction. Four patients exhibited drug related hypercalcemia, 2 complained of severe earache and several had nausea, vomiting and abdominal cramping. There were no objective responses as defined by standard criteria. One patient with thrombocytopenia secondary to documented marrow involvement demonstrated a recovery of platelet count from 9000 to 110,000. 13-cis-Retinoic acid is not of apparent value in women with heavily pretreated breast cancer.

Topics: Breast Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Humans; Isomerism; Isotretinoin; Neoplasm Metastasis; Tretinoin