Summary Retinoids are natural and synthetic derivatives of vitamin A, which can be obtained from animal products (milk, liver, beef, fish oils, and eggs) and vegetables (carrots, mangos, sweet potatoes, and spinach). Retinoids regulate various important cellular functions in the body through specific nuclear retinoic-acid receptors and retinoid-X receptors, which are encoded by separate genes. Retinoic-acid receptors specifically bind tretinoin and alitretinoin, whereas retinoid-X receptors bind only alitretinoin. Retinoids have long been established as crucial for several essential life processes—healthy growth, vision, maintenance of tissues, reproduction, metabolism, tissue differentiation (normal, premalignant cells, and malignant cells), haemopoiesis, bone development, spermatogenesis, embryogenesis, and overall survival. Therefore, deficiency of vitamin A can lead to various unwanted biological effects. Several experimental and epidemiological studies have shown the antiproliferative activity of retinoids and their potential use in cancer treatment and chemoprevention. Emerging clinical trials have shown the chemotherapeutic and chemopreventive potential of retinoids in cancerous and precancerous conditions of the uterine cervix. In this review, we explore the potential chemopreventive and therapeutic roles of retinoids in preinvasive and invasive cervical neoplasia.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(05)70319-3.pdf

Retinoic acid and retinoid receptors: potential chemopreventive and therapeutic role in cervical cancer

Interferon-α (IFNα) is a pleiotropic cytokine with direct and indirect antitumour effects. These include prolongation of the cell cycle time of malignant cells, inhibition of biosynthetic enzymes and apoptosis, interaction with other cytokines, and immunomodulatory and antiangiogenic effects. The first clinical trials in solid tumours used crude preparations of natural IFNα and demonstrated that tumour regressions in solid tumours and haematological malignancies were possible. Since the advent of genetic engineering technology, recombinant (r) IFNα has been widely evaluated in solid tumours. This review discusses the use and potential of rIFNα in solid tumours; the first part focuses on malignant melanoma and metastatic renal cell carcinoma (RCC). In the adjuvant treatment of malignant melanoma, rIFNα has been tested in randomised trials in more than 6000 patients. High-dosage IFNα (≥10MU) prolongs disease-free survival (DFS) but not overall survival (OS). Low-dosage IFNα (≤3MU) has not been shown to prolong DFS or OS, and current data do not support its use outside clinical trials. The latest United Kingdom Co-ordinating Committee on Cancer Research meta-analysis of ten randomised trials that used adjuvant rIFNα has shown that there is a benefit in DFS but not OS. No conclusions can be reached for intermediate-dosage IFNα (5 to 10MU) until the mature results of the European Organization for Research and Treatment of Cancer (EORTC) study 18952 are available. In RCC, current evidence does not support the use of adjuvant IFNα. In metastatic malignant melanoma and RCC, reported response rates to rIFNα are approximately 15%. In a minority of responding patients, however, these responses can be long-standing. In metastatic malignant melanoma, IFNα combined with other cytotoxic agents with or without interleukin-2 has achieved high response rates but has not improved survival. In metastatic RCC, intermediate dosages of rIFNα should be used and therapy should probably be prolonged (≥12 months); response depends on prognostic factors such as good performance status, whereas survival is affected by factors such as low tumour burden. Nephrectomy should therefore be considered in patients with good performance status prior to IFNα immunotherapy in advanced RCC, even in patients with metastatic disease. The toxicity of high-dosage IFNα and the lack of definite benefit on OS with high- or low-dosage IFNα do not support its use outside clinical trials. Data from the ongoing US Intergroup studies, the ongoing EORTC 18991 study (long-term therapy with pegylated IFNα) and mature data from EORTC 18952 (intermediatedosage IFNα) will help establish the role of IFNα as adjuvant therapy in malignant melanoma.

Potential of interferon-alpha in solid tumours: part 1.

How should we grade CIN? The grading of cervical intraepithelial neoplasia (CIN) is problematic. CIN represents a morphological continuum, but biopsies displaying this lesion are classified into two (e.g. Bethesda) or three grade categories, sometimes with poor reproducibility. There are also difficulties in reliably distinguishing low-grade CIN from its reactive simulants. Because of problems with inter- and intra-observer disagreement in the grading of CIN and the diagnosis of low-grade lesions, three expert contributions were commissioned to address the question 'how should we grade CIN?'.

How should we grade CIN

BACKGROUND This study was designed to examine the embryotoxic potential of retinoic acid (RA) at the blastocyst stage and during early post-implantation development of mouse embryos in vitro. METHODS AND RESULTS All-trans retinoic acid (t-RA) was administered to ICR mice embryos at a dose level of 0, 0.001 micromol/l, 0.1 micromol/l and 10 micromol/l throughout in-vitro culture. A total of 404 embryos was randomly assigned to all different dose groups. The percentage of embryos in later stages of development changed depending upon the dose of RA used. Exposure to 10 micromol/l of t-RA at the blastocyst stage, implanted blastocyst stage or early oocyte stage was also found to cause different degrees of retardation of embryo development and embryo death. These findings demonstrate, for the first time, that RA exerts an adverse effect on embryo growth during the early post-implantation stages of development, in comparison with day 3 to day 8 of gestation in vivo. CONCLUSIONS Although isotretinoin (13-cis-retinoic acid) is effective for the therapy of cystic acne and other dermatological disorders, retinoid treatment should be avoided at the early post-implantation stage of gestation.

Effect of retinoic acid on implantation and post-implantation development of mouse embryos in vitro

The effects of interferon (IFN)-alpha, IFN-beta and IFN-gamma on human papillomavirus (HPV) oncogene expression were studied in various cervical carcinoma cell lines containing integrated copies of either HPV type 16 or HPV type 18. The levels of E6 and E7 transcripts were examined 6 h and 30 h after treatment with IFN. In HeLa cells, all three classes of IFNs effected a decrease in the level of HPV-18 E6 and E7 transcripts. On the other hand, none of the IFNs altered the level of these transcripts in C-4II cells. Only IFN-gamma decreased the level of HPV-16 E6 and E7 transcripts in CaSki and HPK1A cells, while IFN-gamma actually increased the level of these transcripts in SiHa cells. This differential IFN regulation of HPV expression in various cervical cancer cell lines may account for the contradictory clinical results observed after treatment of cervical cancer with IFN.

The effects of interferon on the expression of human papillomavirus oncogenes

Recent in vitro studies have suggested a possible therapeutics synergism between α-IFN 2a and 13cRA in certain neoplasias, while encouraging in vivo findings strongly support the enhanced effectiveness of the two agents when used in combination. The specific aim of our study was to evaluate the efficacy and the toxicity of the association of 13cRA and α-IFN 2a in patients with CIN II and CIN III who refused surgical treatment. Twenty-one patients (aged between 25 and 58 years), of which 14 were CIN II and 7 CIN III, entered the study. 13cRA (orally at 0.5-1 mg/Kg/day) and α-IFN 2a (intramuscular at 3 x 10 6 I.U./day for the first 15 days, then 3 times/week for the following four weeks) were administered simultaneously for eight consecutive weeks. 13/21 (62%) histologically verified objective responses (6 complete and 7 partial) were achieved. We also obtained 8 stable diseases. Compliance was generally good and no delays in therapy due to toxicity were recorded (except for two patients presenting WHO degree III cutaneous and mucosal toxicity which regressed one week after suspending treatment). Human Papilloma Virus (HPV) was initially detected in 16/21 (76%) patients, while HPV negativization after treatment was observed in 3/16 (19%). Although preliminary and requiring long-term assessment, the encouraging results of this study confirm the need for further investigation on the role of systemic medical therapy in the treatment of CINs.

Efficacy of the association of 13-cis-retinoic acid (13cRA) and alpha-interferon 2a (α-IFN 2a) in moderate-severe cervical intraepithelial neoplasia (CIN II-III) : A pilot study

S. Rugiati

Papers

Efficacy of the association of 13-cis-retinoic acid (13cRA) and alpha-interferon 2a (α-IFN 2a) in moderate-severe cervical intraepithelial neoplasia (CIN II-III) : A pilot study