isotretinoin and Uterine-Cervical-Neoplasms

Recurrent and metastatic cervical carcinoma has very poor prognosis, mainly because there is no effective systemic therapy which would increase the duration of survival. Biologic agents have recently been found to have activity in cervical carcinoma. The combination of interferon (IFN)-alpha and 13-cis-retinoic acid had additive and synergistic antitumor activity. Both have antiviral, immunoregulatory and antiangiogenic properties, and are known to modulate malignant cell differentiation and proliferation. We report two patients with recurrent squamous cell carcinoma (SCC) of the cervix who had small-volume progressive metastatic disease, and were treated with a combination of IFN-alpha and 13-cis-retinoic acid. The first patient had pelvic lymph node metastases and the other had lung metastases. The previously progressive diseases remained stable for a prolonged period of time, 3 and 4 years, with a good quality of life. These cases suggest the possibility of using IFN-alpha and 13-cis-retinoic acid as a treatment for small-volume residual disease or as postinduction therapy in patients at high risk for disease recurrence.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Female; Humans; Interferon-alpha; Isotretinoin; Pregnancy; Uterine Cervical Neoplasms

Various combinations of retinoids, metabolic and synthetic derivatives of vitamin A, and interferons (IFNs) have demonstrated synergistic antiproliferative, differentiating, and antiangiogenic activity in some human hematologic and solid-tumor systems. This synergistic antitumor activity may be due to enhanced gene expression. In several cell systems, the actions of IFNs are enhanced by differentiation of cells with retinoic acid (RA). Combined RA-IFN effects have been correlated with the induction of higher levels of IFN-stimulated genes than the levels induced by either agent alone. Natural and synthetic retinoids have been found to augment the antiproliferative activity of IFNs in several squamous cell carcinoma (SCC) and breast tumor cell lines. Results of recent clinical trials indicate substantial activity of 13-cis-RA (13cRA) combined with IFN against advanced SCC of the skin and cervix, and possibly against other solid tumors. Two phase II trials have confirmed activity against locally advanced SCC of the cervix. Successful integration of this regimen with radiotherapy appears to be the most probable means of optimizing clinical outcome. Further studies are needed to determine the mechanistic details of the RA-IFN interaction.

Topics: 2',5'-Oligoadenylate Synthetase; Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Clinical Trials, Phase II as Topic; Drug Synergism; Enzyme Induction; Female; Humans; Interferon-alpha; Isotretinoin; Mice; Protein Kinases; Skin Neoplasms; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Preclinical data indicate that the combination of retinoids and interferons have synergistic antiproliferative and differentiating effects in some hematologic and solid tumor models. These observations have led to clinical trials in which 13-cis-retinoic acid (13cRA) 1 mg/kg/day was combined with interferon alpha-2a (IFN alpha) 3 or 6 x 10(6) U/day. The first two such trials produced exciting results: 50% response rate in patients with previously untreated stages IB-IVA cervix cancer and 68% in patients with advanced squamous cell skin cancer. These data led to a number of additional trials of the combination, but the high response rates seen in the initial cervix and skin trials have not been duplicated in the other squamous tumors tested (head and neck, lung, pretreated cervix). In addition, trials in two non-squamous histologies were negative (lung and melanoma). However, the regimen was not always studied in an optimal population of previously untreated patients and the negative results in pretreated cervix patients point to the relevance of this consideration. Nevertheless, the observation that the combination of 13cRA and IFN alpha (both of which bind to specific receptors and change gene expression) is able to induce regression in advanced tumors, must be regarded as highly important. Key questions to be addressed include an understanding of the biologic mechanism of specific tumor sensitivity (why some squamous tumors and not others?), and mechanisms of resistance in sensitive tumor types (e.g. cervix). Such data may lead to trials targeted to tumor types with defined biologic features having a high likelihood of clinical benefit. In the meantime, studies integrating this combination with other active treatment modalities such as radiation is warranted in cervix and skin carcinomas.

Topics: Carcinoma, Squamous Cell; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Neoplasms; Recombinant Proteins; Skin Neoplasms; Uterine Cervical Neoplasms

Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer.. Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate.. Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years.. Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Carcinoma, Squamous Cell; Dermatologic Agents; Female; Follow-Up Studies; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Paclitaxel; Prognosis; Recombinant Proteins; Survival Rate; Uterine Cervical Neoplasms

This study investigated the toxicity and efficacy of a 13-cis retinoic acid, carboplatin, and paclitaxel (Taxol) regimen in 18 patients with recurrent or metastatic squamous cell carcinomas (12 head and neck, 4 cervix, 1 esophagus, and 1 anus). Three patients were treated at each dose level with fenretamide (Accutane) 1 mg/kg/d orally for 14 days, carboplatin AUC of 5 mg/ml.min intravenously (IV) and paclitaxel at a dose of 135, 155, 175, 195, 205, or 225 mg/m(2) IV on day 8 every 4 weeks for 6 cycles. Fifteen evaluable patients had a total of 72 treatment cycles. There were 21 grade III or IV toxicities distributed among all the dose levels, including neutropenia, anemia, thrombocytopenia, elevated prothrombin time/partial thromboplastin time, elevated alkaline phosphatase, weight loss, alopecia, and three deaths from aspiration pneumonia and septic shock. The maximum tolerated dosage included 205 mg/m(2) paclitaxel. There was one complete response, three partial responses, and 2 stable diseases. The three partial responses were in the four patients with cervical cancer. Responses did not correlate with expression of retinoic acid receptor subtypes. Toxicity profiles and overall response rates were comparable to prior studies with similar chemotherapy regimens alone. The data support further study in a phase II trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Drug Synergism; Female; Head and Neck Neoplasms; Humans; Isotretinoin; Male; Middle Aged; Paclitaxel; Remission Induction; Uterine Cervical Neoplasms

Topics: Administration, Oral; Adolescent; Adult; Disease Progression; Drug Administration Schedule; Female; HIV Infections; Humans; Isotretinoin; Neoplasms, Squamous Cell; Uterine Cervical Neoplasms

To estimate the efficacy of isotretinoin for prevention of progression of low-grade squamous intraepithelial lesions (SIL) of the cervix to high-grade lesions or invasive cervical cancer; to estimate the regression rate of low-grade SIL with isotretinoin and the toxicity of isotretinoin in this setting; and to correlate serum CD4 levels with progression of low-grade SIL.. A randomized, phase III, observation-controlled, multicenter trial was performed in which 117 human immunodeficiency virus (HIV)-positive women with low-grade SIL of the cervix received either oral isotretinoin at 0.5 mg/kg per day for 6 months or observation. Papanicolaou smears and colposcopy/biopsy were done at regular intervals during follow-up. The primary endpoint was progression to high-grade SIL or cervical cancer.. Twenty-one of 102 women (20.6%) completing follow-up experienced progression to high-grade SIL, 13 in the observation group and eight in the isotretinoin group. This difference was not significant (P =.29). No cases of invasive cancer were seen. Baseline CD4 levels were lower than anticipated (median 329 cells/mm(3)), but not associated with time to progression (P =.36). Most subjects (63 of 102, 61.7%) used highly active antiretroviral therapy. Subjects under age 30 were more likely to progress than those older than 30 (P =.046).. Isotretinoin was not associated with longer time to progression of low-grade SIL. This appears to be a chronic condition in HIV-positive women, with a low risk of progression and significant rate of resolution. As in the general population, observation without excisional therapy may be appropriate for HIV-positive women with low-grade SIL.

Topics: Adult; CD4 Lymphocyte Count; Disease Progression; Female; HIV Infections; Humans; Isotretinoin; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Standard treatment with radiotherapy for locally advanced cancer of the uterine cervix has a response rate of less than 50%. Recently, concurrent chemotherapy with radiotherapy was introduced into the clinic but is value remains controversial. Interferon and retinoic acid possess antiproliferative, immunomodulatory, and antineoplastic activities. The combination of interferon and retinoic acid has significant activity in patients with squamous cell carcinoma. These compounds may also potentiate radiation cytotoxicity. This pilot study aimed to assess the clinical efficacy and tolerability of the combination of interferon-alpha 2a, 13-cis-retinoic acid and radiotherapy. Patients with locally advanced carcinoma of the cervix were treated at Severance Hospital, Yonsei University College of Medicine. Fifteen patients received the combination of interferon-alpha 2a, 13-cis-retinoic acid and radiotherapy. Twelve patients treated in previous years with comparable radiotherapy and concurrent chemotherapy served as historical controls.. (1) Interferon-alpha 2a, 13-cis-retinoic acid and radiotherapy resulted in a 47% response rate (33% complete remissions) while patients treated with concurrent chemoradiotherapy had a 42% response rate (17% complete remissions) (2). Major toxicity of interferon-alpha 2a, 13-cis-retinoic acid and radiotherapy was fever (60%). There was no grade 3 or 4 toxicity.. Systemic interferon-alpha 2a, 13-cis-retinoic acid and radiotherapy is an active and tolerable therapy for locally advanced cervical cancer. Randomized studies are required to define the role of bioradiotherapy in the treatment of advanced cervical cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Female; Humans; Interferon-alpha; Isotretinoin; Middle Aged; Pilot Projects; Radiotherapy, Adjuvant; Treatment Outcome; Uterine Cervical Neoplasms

We have evaluated the tumor tissue pO2 in cervical cancers in patients treated with 13-cis-retinoic acid and interferon-alpha-2a prior to and during radiotherapy.. From June 1995 through April 1997, 22 patients with squamous cell carcinoma FIGO IIB/III of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-alpha-2a (IFN-alpha-2a) as part of a phase-II protocol. cRA/IFN-alpha-2a started 14 days prior to radiotherapy (1 mg per kilogramme body weight cRA orally daily plus 6 x 10(6) IU IFN-alpha-2a subcutaneously daily). After this induction period, standard radiotherapy was administered (external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus HDR-brachytherapy). During radiotherapy, cRA/IFN-alpha-2a treatment was continued with 50% of the daily doses. Tumor tissue pO2-measurements were performed prior to and after the cRA/IFN-induction period as well as at 20 Gy and at the end of radiotherapy with an Eppendorf-pO2-histograph.. In 11 out of the 22 patients, pO2-measurements were performed prior to the cRA/IFN-induction therapy. The median pO2 of these untreated tumors was 17.7 +/- 16.3 mm Hg. The relative frequency of hypoxic readings with pO2-values below 5 mm Hg ranged from 0% to 60.6% (mean 24.3 +/- 21.0%). After the 2-week induction period with cRA/IFN, the median pO2 had increased from 17.7 +/- 16.3 mm Hg to 27.6 +/- 19.1 mm Hg (not significant). In all 5 patients with hypoxic tumors prior to cRA/IFN (median pO2 of 10 mm Hg or less), the median pO2 was above 20 mm Hg after the 2-week cRA/IFN-induction. In this subgroup of hypoxic tumors, the median pO2 increased from 6.3 +/- 2.7 mm Hg to 27.0 +/- 5.6 mm Hg (p = 0.004, t-test for paired samples). The frequency of hypoxic readings (pO2-values < 5 mm Hg) decreased from 44.7 +/- 17.1% to 2.0 +/- 2.5% (p = 0.012, t-test for paired samples). There was, however, no obvious volume reduction after 14 weeks of cRA/IFN on clinical examination. A complete clinical remission of the local tumor was observed in 19/22 patients after radiotherapy and additional cRA/IFN-alpha-2a-treatment. In primarily hypoxic tumors (with a median pO2 below 10 mm Hg prior to treatment), 4/5 achieved complete remission.. Pretreatment with cRA/IFN improves oxygenation of primarily hypoxic cervical cancers. The mechanisms of action remain unclear and further investigation of the combination regimen is recommended.

Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Hypoxia; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Keratolytic Agents; Middle Aged; Oxygen; Radiotherapy Dosage; Recombinant Proteins; Time Factors; Uterine Cervical Neoplasms

From January 1993 through January 1996, 37 patients with unresectable squamous carcinoma of the cervix were entered on study and scheduled to receive oral isotretinoin 1 mg/kg per day with subcutaneous alpha interferon 6,000,000 units/day. A course was defined as 4 continuous weeks of therapy. The mean number of four-course cycles delivered was 1.8. One patient was ineligible because of wrong cell type and two were never treated. Thus, 34 patients were evaluable for toxicity. Eight patients were inevaluable for response. Five did not receive a complete 4-week course and three did not have additional tumor measurements; thus 26 were evaluable for response. Prior radiotherapy had been given to 25 patients and prior chemotherapy to 23 patients. There was no grade 4 neutropenia. The incidence of Gynecologic Oncology Group (GOG) grade 3 granulocytopenia and thrombocytopenia was 8.8% and 5.8%, respectively. Six patients (17.6%) developed grade 3 or worse nausea and vomiting. Four (11.7%) patients developed grade 3 neurologic symptoms. There were no complete responses and one partial response. The overall response rate was 3.8% (95% confidence interval, 0.1-19.6%). In this pretreated population, isotretinoin and alpha interferon in the dose and schedule employed exhibit minimal activity.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Therapy, Combination; Female; Humans; Interferon-alpha; Isotretinoin; Keratolytic Agents; Middle Aged; Neoplasm Recurrence, Local; Uterine Cervical Neoplasms

Preclinical and clinical data support the study of retinoids and interferon-alpha (IFN-alpha) in advanced squamous cell carcinoma of the uterine cervix (SCC). This phase II randomized trial of the Southwest Oncology Group sought to estimate the response rate for IFN-alpha plus either 13-cis-retinoic acid (13cRA) or all-trans-retinoic acid (ATRA) in women with recurrent cervical SCC.. Eligibility for this trial required bidimensionally measurable locally recurrent or metastatic squamous or adenosquamous carcinoma of the uterine cervix; SWOG performance status of

Topics: Adult; Aged; Carcinoma, Squamous Cell; Female; Humans; Interferon-alpha; Isotretinoin; Middle Aged; Neoplasm Recurrence, Local; Tretinoin; Uterine Cervical Neoplasms

Retinoids are strong inhibitors of epithelial cancer promotion and progression in experimental carcinogenesis. Recently, therapeutic trials of retinoids have demonstrated activities in cervical cancer and precancerous lesion of cervix. Our purpose was to determine whether additional administration of 13-cis-retinoic acid would improve the treatment effect of neoadjuvant chemotherapy in patients with squamous cell carcinoma of the cervix. From January 1994 through January 1995, 40 patients with invasive cervical cancer were enrolled in this prospective study and randomized into the two groups. Group 1 had neoadjuvant chemotherapy alone and group 2 had neoadjuvant chemotherapy plus 13-cis-retinoic acid (RA) at a dosage of 1 mg/kg/day for 1 month. Patients in group 1 and group 2 were similar with respect to age, parity, clinical stage, and histological subtype. Therapeutic responses were compared using Fisher's exact test, Mann-Whitney test, and Wilcoxon signed-rank test. RA increased the complete response rate of neoadjuvant chemotherapy from 0% in group 1 to 5% in group 2. However, a difference of overall clinical response rate between the two groups was not evident. The drug toxicities in group 1 and group 2 included anemia in 30.0% and 23.7%, leukopenia in 6.7% and 15.2%, and hepatotoxicity in 6.7% and 6.8%, respectively. More frequent incidence of mucocutaneous side effects was seen in group 2 than group 1, but these side effects were mild and reversible. The clinical response rate achieved in this trial indicates that the combination of 13-cis-retinoic acid and neoadjuvant chemotherapy, at least when used on the schedule reported herein, is not superior to treatment of neoadjuvant chemotherapy alone for patients with squamous cell carcinoma of the cervix. However, a single patient achieved a complete response on this therapy, and the impact of such a treatment on survival needs to be explored.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Female; Humans; Isotretinoin; Middle Aged; Prospective Studies; Uterine Cervical Neoplasms; Vincristine

The combination of 13-cis-retinoic acid (13-cRA) and interferon (IFN)-alpha 2a has been reported to be highly active in previously untreated squamous carcinoma of the cervix. In this phase II study, 13-cRA was given at a dose of 1 mg/kg/day and IFN-alpha 2a was given subcutaneously at a dose of 3 million units/m2/day. Thirteen of 14 patients enrolled in this study are evaluable for response and toxicity. There were no complete or partial responses. Ten patients had progressive disease and the remaining three had stable disease. Principle toxicities were fatigue, nausea, and vomiting. This regimen appears cross-resistant with radiotherapy and/or platinum-based cytotoxic therapy in heavily pretreated patients with squamous carcinoma of the cervix.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Middle Aged; Recombinant Proteins; Uterine Cervical Neoplasms

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Middle Aged; Recombinant Proteins; Uterine Cervical Neoplasms

Chemotherapeutic study of cervical squamous cell carcinoma has shown some positive results. Complete plus partial (overall) response rates of 15%-35% (complete response rate, less than 5%) were achieved with the use of a small number of cytotoxic single agents in patients with advanced disease. In addition, overall response rates of 60%-70% (complete response rates, 10%-20%) were achieved with cisplatin-based, multiagent regimens in patients with primary, locally advanced disease. However, the lack of clear evidence that existing chemotherapy can achieve a survival benefit, coupled with the worldwide annual deaths of hundreds of thousands of women from cervical cancer, indicates the urgent need for effective systemic therapy for this disease.. In view of the preclinical and clinical evidence that supports testing of the novel combination of 13-cis-retinoic acid (13-cRA) plus interferon-alpha (IFN-alpha) in cervical squamous cell carcinoma, we conducted a phase II study of this regimen in locally advanced disease.. Twenty-six patients with untreated, locally advanced squamous cell carcinoma of the cervix were treated daily for at least 2 months with oral 13-cRA (1 mg/kg) and subcutaneous recombinant human IFN alpha-2a (6 million units). In 21 patients (81%), the disease was stage II or higher.. Thirteen patients (50%) experienced major responses (tumor regression greater than or equal to 50%) in association with resolution of symptoms; one achieved complete response, and 12 experienced partial response. Seven with partial response are improving further, four are being maintained in partial response, and one responder has relapsed during therapy. The response rate is 58% (11 of 19) in patients with stage IIB or higher disease and 66% (10 of 15) in patients with bulky disease (at least one dimension greater than or equal to 10 cm). Of the 13 non-responders, nine have stable disease and four have had disease progression during therapy. Toxicity was minimal.. These preliminary results indicate that systemic 13-cRA plus IFN alpha-2a is a highly active, well-tolerated therapy for locally advanced cervical cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug Evaluation; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Middle Aged; Recombinant Proteins; Remission Induction; Uterine Cervical Neoplasms

Topics: Administration, Oral; Adult; Antineoplastic Agents; Chemoprevention; Colposcopy; Conization; Dose-Response Relationship, Drug; Female; Humans; Isotretinoin; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Treatment Failure; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

The purpose of this study was to determine whether the progression of low-grade squamous intraepithelial lesions of the cervix in women with the human immunodeficiency virus can be predicted reliably by standard cytologic testing.. As part of a previously reported trial, 288 biopsy specimens were collected from 117 women with the human immunodeficiency virus. These specimens underwent central and local interpretation, which were compared and correlated with cytologic results. Ninety-two subjects had matched cytologic/histologic pairs at study termination, which were compared to determine whether cytologic testing was predictive of progression.. Of the central histologic interpretations, 26 of 288 interpretations (9%) differed from local results, 97 of 246 cytologic/histologic pairs (39%) were discordant, and 21 subjects had progression to high-grade squamous intraepithelial lesions by histologic evidence. Cytologic testing showed high-grade squamous intraepithelial lesions in 4 of 21 specimens (sensitivity, 19%). The remaining cytologic specimens were either low-grade squamous intraepithelial lesions or were normal.. This substudy of pathologic results from a randomized clinical trial suggests that, although the risk of progression of low-grade squamous intraepithelial lesions is low, follow-up cytologic testing is unreliable. Colposcopic evaluation with directed biopsies should be continued.

Topics: Antineoplastic Agents; Biopsy; Carcinoma, Squamous Cell; Cervix Uteri; Clinical Trials, Phase III as Topic; Colposcopy; Disease Progression; Female; Follow-Up Studies; HIV Infections; Humans; Isotretinoin; Predictive Value of Tests; Prognosis; Randomized Controlled Trials as Topic; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaginal Smears

Combined use of 13-cis-retinoic acid (cRA) and interferon-alpha2a (IFNalpha) induced significant radiosensitization in human cervical cancer ME-180 cell line, whereas it failed to achieve similar radiation enhancement in HeLa cells. The differential radiosensitization could be from the difference of retinoic acid receptor (RAR) expression because RAR-beta was highly expressed in ME-180 cells in contrast to the HeLa cells where RAR-beta was not detectable. We examined the role of this gene in mediating radiosensitization by cRA and IFNalpha, and explored the mechanism of radiation-induced cell killing.. Human cervical cancer cell lines, ME-180 and HeLa, were treated with cRA and IFNalpha followed by radiation. Apoptosis and radiosensitization were quantitated by TUNEL assay (in situ DNA nick end labeling) and colony-forming ability of surviving cells. The cells were transfected with bcl-2 gene and RAR-beta gene to test the role of these genes in mediating radiosensitization and apoptosis.. Synergistic radiosensitization and apoptosis was observed by combined use of cRA and IFNalpha with radiation in ME-180 cells which express high level of RAR-beta mRNA, whereas these were not seen in HeLa cells where RAR-beta mRNA is not detectable. Both radiosensitization and apoptosis were abolished by bcl-2 gene in ME-180 cells. RAR-beta gene transfection induced similar radiation enhancement and apoptosis in HeLa cells.. Apoptosis and radiation response were enhanced in the cells with high level of RAR-beta mRNA expression. The RAR-beta gene appears to mediate the radiation-induced apoptosis by cRA and IFNalpha. These findings indicate that presence of RAR-beta in the cancer cells could be exploited for patient selection in using these drugs for apoptosis and radiosensitization.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Combined Modality Therapy; Female; HeLa Cells; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Radiation Tolerance; Receptors, Retinoic Acid; Recombinant Proteins; Transfection; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Significant antitumor activity has been reported with the combined use of 13-cis-retinoic acid (cRA) and interferon-alpha2a (IFN-alpha) in the treatment of advanced-stage cervical cancers and skin cancers. Since IFN-alpha has been shown to be a modest radiation enhancer for selected malignant tumor cells and the cytotoxic activity is more enhanced by combining cRA and IFN-alpha, we hypothesized that the exposure of selected human carcinoma cells to combined cRA and IFN-alpha would render the cells highly radiosensitive.. Two human cervical carcinoma cell lines, ME-180 and HeLa-S3, were chosen for the present study because of the different characteristics of the retinoic acid receptor status of the cell lines. To demonstrate the effects of combined cRA and IFN-alpha treatment on radiation response, we exposed the cells to cRA, IFN-alpha, or a combination of the drugs for 72 h before radiation. Experiments were carried out at minimally cytotoxic concentrations of the drug for radiation studies. End points of the study were cell growth inhibition and clonogenic ability of the single-plated cells. Effects of cRA and IFN-alpha on radiation response were quantitatively analyzed by constructing the radiation cell survival curves of ME-180 and HeLa cells.. ME-180 cells exhibited varying degrees of cytotoxicity with cRA and IFN-alpha, while HeLa cells showed no toxic effects with the same treatment. Combined treatment of cRA and IFN-alpha produced an additive cytotoxic effect in ME-180 cells. Radiosensitization was minimal when ME-180 cells were treated with either cRA or IFN-alpha before radiation. When ME-180 cells were exposed to 10 microM cRA for 48 h and 1000 U/ml IFN-alpha for 24 h prior to radiation, there was a significant enhancement in radiation-induced cell killing; the dose modification factor was 2.1 +/- 0.9 at the 1% cell-survival level. On the other hand, HeLa-S3 cells exhibited no increased cytotoxicity or radiation enhancement under the same experimental conditions.. The present data provide a radiobiological basis for using cRA and IFN-alpha as a combination radiosensitizer in selected human carcinoma cells.

Topics: Antineoplastic Agents; Cell Division; Female; HeLa Cells; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Radiation-Sensitizing Agents; Recombinant Proteins; Tumor Cells, Cultured; Uterine Cervical Neoplasms

To evaluate prognostic importance of p53, PCNA and vascularization alteration in patients with locally advanced cervical squamous cell carcinoma (SCC) after combination therapy with 13-cis-retinoic acid (13cRA) and interferon-alpha 2a (IFN-alpha 2a).. 13cRA and IFN-alpha 2a were administered to patients with locally advanced cervical SCC. Formalin fixed, paraffin embedded tissues sections obtained at pre- and post-therapy, respectively, were stained immunohistochemically with anti-p53, anti-PCNA and anti CD31.. p53 alteration was demonstrated in 5/10 patients and 3/10 patients pre- and post-therapy, respectively. There was no correlation between p53 alteration and prognosis. After therapy, two patients with complete response had lower PCNA expression whereas the non-responders demonstrated the opposite result. The vascularization showed a correlation with PCNA and prognosis. In the response group, patients had lower microvessel count while the metastatic group exhibited higher count.. The present study suggests that p53 alteration is neither related to the prognosis of cervical SCC nor is it influenced by the combination therapy while PCNA expression and vascularization might be constitute potential markers for tumorigenesis, prognosis and responsiveness to this novel regimen.

Topics: Adult; Antineoplastic Agents; Carcinoma, Squamous Cell; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Middle Aged; Neovascularization, Pathologic; Prognosis; Proliferating Cell Nuclear Antigen; Recombinant Proteins; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Combined Modality Therapy; Feasibility Studies; Female; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Uterine Cervical Neoplasms

Topics: Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Male; Uterine Cervical Neoplasms

Patients with metastasising carcinoma of the uterine cervix or recurrent disease, in whom local treatment as surgery or radiotherapy has failed, are still an unsolved problem. Platinum-based multi-agent chemotherapies achieve overall response rates up to 60%, but side effects are serious and so far no survival benefit has been proven. Recent publications report on a synergistic effect of combination therapy using 13-cis-retinoic acid and interferon alpha-2 a in the treatment of squamous cell carcinoma of the cervix. In a pilot study we include 6 patients with locally recurrent or metastasising squamous cell carcinomas, five of the uterine cervix, one of the vulva. The systemic therapy consisted of-orally administered 13-cis-retinoic acid (80 mg q. d.) and subcutaneously injected interferon alpha-2 a (6 x 10(6) I.E. q. d.). All patients were primarily treated by surgical and/or radiation therapy. In each case chemotherapy had been either already performed or rejected by the patient. Median duration of treatment was 52 days, median survival time 107 days. Out of 6 patients 3 experienced progression of disease uninfluenced by therapy. One patient with multiple subcutaneous lymph node metastases showed mixed response for a short period of 3 weeks before progression and eventual death. One patient had no change or disease for 13 months with subsequent progression and eventual death after 22 months. One patient could not be evaluated for an allergic reaction after only 15 days of treatment. Other side effects were "flu-like symptoms", skin irritations, conjunctivitis sicca and chileitis, all WHO 1-2. Overall toxicity must be rated low compared to standard chemotherapy, but is not negligible. In our study the positive reports in literature concerning the treatment of primary advanced cervical cancer and recurrent advanced carcinoma of the skin could not be reproduced. This might be due to the small number of cases, which is a common problem in immunotherapeutic studies. Moreover, very unfavourable patient selection criteria in our study compared to primarily untreated patients may also have contributed to different response rates. However, in our opinion the tested regimen cannot be considered sufficiently effective in patients suffering from pretreated, recurrent squamous cell carcinoma of the cervix or vulva.

Topics: Administration, Oral; Adult; Aged; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Isotretinoin; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Pilot Projects; Recombinant Proteins; Survival Rate; Uterine Cervical Neoplasms; Vulvar Neoplasms

The important therapeutic activity of 13-cRA and IFN-alpha-2a in carcinoma of squamous cells, cervical, without previous treatment, is confirmed. An unexpected result was the early toxicity of the biologic agents on the colon mucosa when they are combined with radiotherapy.

Topics: Adult; Aged; Brachytherapy; Carcinoma, Squamous Cell; Cesium Radioisotopes; Cobalt Radioisotopes; Colon; Combined Modality Therapy; Evaluation Studies as Topic; Female; Humans; Interferon alpha-2; Interferon-alpha; Intestinal Mucosa; Isotretinoin; Middle Aged; Radiotherapy; Radiotherapy Dosage; Recombinant Proteins; Uterine Cervical Neoplasms

The effects of retinoids including all-trans-retinoic acid (ATRA), 13-CIS-RETINOIC ACID (13CRA), and N-(4-hydroxyphenyl)retinamide (4-HPR) on several cervical carcinoma cell lines in culture were investigated as a prelude to investigating the mechanisms underlying the chemopreventive potential of retinoids in cervical cancer. We found that when used at a concentration of 1 microM, 13CRA and ATRA inhibited the proliferation of three cell lines (ME-180 [HPV 68], SiHa [HPV 18], and HT-3 [HPV-]) by about 80% after a seven-day treatment. Three other cell lines (MS-751 [HPV 18], HeLa [HPV 18], C-33A [HPV-]) were moderately inhibited (30-48%), and two (C-4 II [HPV 18], CaSki [HPV 16]) responded poorly (< 25% inhibition). 4-HPR failed to inhibit the growth of any of these cell lines when used at 1 microM; however, when used at 5 or 10 microM, it induced apoptosis as evidenced by DNA fragmentation in several of the cell lines and was more potent in this effect than 10 microM ATRA. Retinoids that induce apoptosis in malignant cells may be able to exert similar effects on premalignant cells. Such retinoids would be expected to exhibit greater potency as chemopreventive agents than retinoids that exert only cytostatic effects.

Topics: Anticarcinogenic Agents; Apoptosis; Cell Division; DNA Damage; Drug Evaluation, Preclinical; Female; Fenretinide; Humans; Isotretinoin; Retinoids; Tretinoin; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Discussions from a recent cancer conference held in May of 1995 are summarized in the following areas: 1) the effect of mitoguazone in relapsed non-Hodgkin's lymphoma; 2) the addition of ddI or ddC to chemo for advanced Kaposi's sarcoma (KS); 3) progress in use of three new anti-KS agents; 4) the effectiveness of phototherapy as palliation for KS; and 5) reasons why HIV prevalence is probably underestimated in women. Additionally, the paper reviews the Lymphoma Project Report which analyzed the epidemiology, pathogenesis, diagnosis, clinical manifestations, molecular characteristics, prognostic factors, and treatment of AIDS lymphoma. The following were among the findings: a regimen of doxorubicin, bleomycin, and vincristine with either ddI or ddC was well tolerated and evoked antitumor responses in patients with KS; 9-cis-retinoic acid and beta-human chorionic gonadotropin can induce remission of KS lesions; photodynamic therapy is an effective palliative therapy for some people with KS, but doses above 300 joules/cm2 result in scarring; and most American women who die of cervical cancer probably also have HIV infection according to a clinician from State University of New York in Brooklyn. The article concludes with a discussion of the differences between the focus of HIV research and HIV meetings for the ASCO assembly and the AIDS community.

Topics: Acquired Immunodeficiency Syndrome; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Chorionic Gonadotropin; Female; Humans; Isotretinoin; Lymphoma, AIDS-Related; Lymphoma, Non-Hodgkin; Mitoguazone; Paclitaxel; Palliative Care; Photochemotherapy; Recurrence; Sarcoma, Kaposi; Uterine Cervical Neoplasms

Topics: Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Male; Neoplasms; Papillomaviridae; Papillomavirus Infections; Skin Neoplasms; Tumor Virus Infections; Uterine Cervical Neoplasms

Topics: Animals; Etretinate; Female; Folic Acid; Humans; Isomerism; Isotretinoin; Neoplasms; Neoplasms, Experimental; Skin Neoplasms; Tretinoin; Uterine Cervical Neoplasms; Vitamin A; Vitamin E