isotretinoin and Papilloma

The purpose of this study was to evaluate adjuvant drug therapies combined with standard laser excision in the treatment of recurrent respiratory papillomatosis. Previous studies have presented conflicting data on the efficacy of various treatments, including interferon and isotretinoin. A retrospective study of 34 patients with moderate to severe papillomatosis who underwent both laser surgery and adjuvant therapy was therefore performed. All patients were treated with interferon. Five interferon failures received isotretinoin, and three with recalcitrant disease received methotrexate. Interferon produced a complete response in 16 patients and partial response in 12 patients. Juvenile-onset disease had a slightly higher response to interferon than adult-onset disease. isotretinoin produced no response in all five patients. Methotrexate demonstrated a marked improvement in both severity of disease and treatment interval in all three patients. Serious side effects were limited to one interferon patient with febrile seizures, which resolved with discontinuation of therapy. We conclude that adjuvant therapy including interferon and methotrexate is clearly of benefit in the treatment of patients with respiratory papillomatosis. A detailed approach to surgery combined with an interferon dosing regimen is presented. Further study of methotrexate appears warranted.

Topics: Adolescent; Adult; Age of Onset; Aged; Chemotherapy, Adjuvant; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Interferons; Isotretinoin; Laryngeal Neoplasms; Laser Therapy; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Papilloma; Remission Induction; Retrospective Studies; Tracheal Neoplasms

Confluent and reticulated papillomatosis is most probably a disorder of keratinization rather than a fungal infection. We describe an 18-year-old man who was effectively treated with high-dose oral isotretinoin. Our review of the literature on confluent and reticulated papillomatosis refutes previously accepted epidemiologic data.

Topics: Administration, Oral; Adult; Female; Humans; Isotretinoin; Male; Papilloma; Skin

Topics: Acne Conglobata; Acne Vulgaris; Animals; Cysts; Dermatologic Agents; History, 20th Century; Humans; Isotretinoin; Mice; Models, Animal; Papilloma; Placebo Effect; Skin Neoplasms; Vitamin A

Malignant acanthosis nigricans (MAN) with oral florid papillomatosis is a rare paraneoplastic condition affecting the skin and mucocutaneous tissues associated with an underlying malignancy. It is characterized by proliferation of keratinocytes resulting in papillomatous change and hyperpigmentation of the skin and multiple confluent warty or verrucous lesions of the oral mucous membranes. The oral involvement can interfere with the patient's ability to eat and drink. There is no specific therapy for this complication. Treatment of the underlying malignancy can lead to improvement of symptoms, but the degree of improvement varies. Here, the authors present a case of MAN with oral florid papillomatosis associated with gastric adenocarcinoma that was treated with oral retinoids resulting in significant clinical improvement of the hyperkeratosis and hyperpigmentation as well as improved patient functionality.

Topics: Acanthosis Nigricans; Adenocarcinoma; Adult; Biopsy; Female; Humans; Isotretinoin; Keratolytic Agents; Lip; Palliative Care; Papilloma; Paraneoplastic Syndromes; Skin; Stomach Neoplasms; Tongue

Topics: Biopsy; Dermatologic Agents; Dose-Response Relationship, Drug; Humans; Isotretinoin; Male; Middle Aged; Papilloma; Treatment Outcome

Confluent and reticulated papillomatosis is an uncommon dermatosis of unknown etiology which is often difficult to diagnose. Lesions appear on the mid-trunk and affect mostly young females. We report a 15-year-old girl with typical clinical and histologic features of this rare disorder in whom the lesions rapidly improved after minocycline therapy. Topical treatment with isotretinoin and erythromycin was ineffective.

Topics: Administration, Oral; Administration, Topical; Adolescent; Biopsy; Cyproterone Acetate; Diagnosis, Differential; Erythromycin; Female; Humans; Isotretinoin; Minocycline; Papilloma; Recurrence; Skin; Skin Neoplasms

Topics: Aged; Aged, 80 and over; Chemotherapy, Adjuvant; Female; Humans; Isotretinoin; Neoplasm Recurrence, Local; Papilloma; Tracheal Neoplasms

We recently synthesized several conformationally constrained retinoic acid (RA) analogues [8-(2'-cyclohexen-1'-ylidene)-3, 7-dimethyl-2,4,6-octatrienoic acids with different alkyl substituents at 2' (R1) and 3' (R2) positions on the cyclohexene ring] (Muccio et al. J. Med. Chem. 1996, 39, 3625) as cancer chemopreventive agents. UAB8 (R1 = Et; R2 = iPr), which contains sufficient steric bulk at the terminal end of the polyene chain to mimic the trimethylcyclohexenyl ring of RA, displayed biological properties similar to those of RA. To explore the efficacy of this retinoid in acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML), we evaluated UAB8 isomers in in vitro assays which measure the capacity of retinoids to inhibit aberrant myeloid colony growth from blood or bone marrow cells obtained from human JMML patients and in assays measuring the potential of retinoids to differentiate NB4 cells (an APL cell line). Both (all-E)- and (13Z)-UAB8 were 2-fold more active than RA in the NB4 cell differentiation assay; however, only (all-E)-UAB8 had comparable activity to the natural retinoids in the JMML cell assays. These results were compared to the biological effectiveness of a new retinoid, UAB30 [8-(3', 4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4, 6-octatrienoic acid], which had different nuclear receptor binding and transactivational properties than UAB8. Relative to (all-E)-RA and (all-E)-UAB8, (all-E)-UAB30 bound well to RARalpha but did not activate transcription-mediated RARalpha homodimers, even though it was effective in RARbeta- and RARgamma-mediated transactivational assays. In APL assays, this retinoid had much reduced activity and was only moderately effective in JMML assays and in cancer chemoprevention assays.

Topics: Animals; Antineoplastic Agents; Cell Line; Chickens; Child; Fatty Acids, Unsaturated; HL-60 Cells; Humans; In Vitro Techniques; Leukemia, Myelomonocytic, Chronic; Leukemia, Promyelocytic, Acute; Mice; Molecular Conformation; Naphthalenes; Papilloma; Radioligand Assay; Receptors, Retinoic Acid; Skin; Skin Neoplasms; Stereoisomerism; Transcription, Genetic; Tretinoin; Tumor Stem Cell Assay

We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the ch

Topics: Animals; Anticarcinogenic Agents; Cell Nucleus; Mice; Models, Molecular; Molecular Conformation; Molecular Structure; Papilloma; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Skin Neoplasms; Stereoisomerism; Structure-Activity Relationship; Thermodynamics; Transcription Factors; Transcription, Genetic

Topics: Administration, Cutaneous; Administration, Oral; Adolescent; Dermatologic Agents; Emollients; Female; Humans; Isotretinoin; Keratolytic Agents; Lactic Acid; Papilloma; Remission Induction; Skin Neoplasms

Retinoic acid has been advocated for use in several premalignant and malignant epithelial lesions of the head and neck, including benign recurrent respiratory papillomatosis, with varying results. We describe a 24-year-old man with extensive tracheoesophageal and bronchoalveolar papillomatosis that degenerated into squamous cell carcinoma. Multiple endoscopic carbon dioxide laser excisions, at one point performed on a weekly basis, as well as a prolonged trial of interferon, failed to control the progression of his disease. Isotretinoin (13-cis-retinoic acid) therapy (1 mg/kg per day) was instituted, with dramatic clinical, radiographic, and functional improvement. The patient experienced no significant toxic effects and required no endoscopic procedures over a 6-month period. We propose that isotretinoin may be an effective adjuvant therapy for aggressive respiratory papillomatosis.

Topics: Administration, Oral; Adult; Carcinoma, Squamous Cell; Humans; Isotretinoin; Male; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Papilloma; Radiography; Respiratory Tract Neoplasms

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Neoplasm Recurrence, Local; Papilloma; Pilot Projects; Prospective Studies; Recombinant Proteins; Respiratory Tract Neoplasms; Severity of Illness Index; Treatment Outcome

Topics: Adult; Humans; Isotretinoin; Male; Neoplasms, Multiple Primary; Papilloma; Skin Neoplasms

The present study was designed to determine the effects of dietary 13-cis-retinoic acid and retinyl palmitate on mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). Female CD-1 mice were initiated with 150 nmol of 7,12-dimethylbenz(a)anthracene and promoted twice weekly with 8 nmol of TPA. Diets supplemented with retinyl palmitate to yield 60,000 or 200,000 IU or 700,000 for 5 wk followed by 350,000 IU per kg of diet (700,000/350,000) fed to mice during tumor promotion resulted in 9%, 37%, and 65% inhibition of the papilloma yield, respectively, at 21 wk of promotion. Although topical applications of 13-cis-retinoic acid have been almost as effective as retinoic acid in preventing the appearance of mouse skin tumors, dietary 13-cis-retinoic acid at 200,000 or 700,000 IU per kg of diet resulted in no reduction in papilloma yield but did result in a dose-dependent decrease in the tumor burden (weight of tumors per mouse). Therefore, dietary retinyl palmitate yielded a dose-dependent inhibition of the number and weight of tumors promoted by TPA, whereas dietary 13-cis-retinoic acid resulted in a decrease in weight but not in number of tumors promoted by TPA.

Topics: Administration, Cutaneous; Animals; Cell Transformation, Neoplastic; Diet; Diterpenes; Dose-Response Relationship, Drug; Female; Isotretinoin; Mice; Papilloma; Retinyl Esters; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin; Vitamin A

The effects of dietary supplementation of 13-cis-retinoic acid (13-cis-RA) and alpha-difluoromethylornithine (DFMO) in the drinking water on 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation was determined. Administration of 13-cis-RA in the diet and DFMO in the drinking water was started 1 week and 2 days before the first TPA application to the dimethylbenz[a]anthracene-initiated skin of either female CD-1 or SENCAR mice, respectively. Dietary 13-cis-RA failed to inhibit both the tumor yield and the incidence; papillomas per mouse at 0, 5, 50, 100 and 200 mg/kg diet 13-cis-RA doses were 25, 30, 22, 28 and 25 respectively at 18 weeks of promotion treatment and at all doses 100% of the mice bore papillomas. However, dietary 13-cis-RA dramatically reduced the size of skin tumor promoted with TPA. 13-Cis-RA at doses of 5, 50, 100 and 200 mg/kg diet inhibited skin papillomas (greater than 4 mm diameter) per mouse by 28, 55, 76 and 93%, respectively. Retinoid treatment did not affect body weight gains and the survival was more than 80% in all groups. In accord with our previous findings, DFMO when given in drinking water, was a very effective inhibitor of mouse skin tumor promotion by TPA; DFMO at 0.25% concentration inhibited the number of papillomas by 50%. Inhibition of skin tumor promotion by combined treatments with dietary 13-cis-RA (100 mg/kg) and DFMO (0.25%) in the drinking water was possibly additive. The retinoid and DFMO preclude TPA-increased ornithine decarboxylase (ODC) activity and the accumulation of putrescine by differential effects on ODC, an enzyme associated with skin tumor promotion by TPA.

Topics: Animals; Diet; Eflornithine; Female; Isotretinoin; Mice; Mice, Inbred Strains; Ornithine; Ornithine Decarboxylase; Papilloma; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Laryngeal papillomatosis often involves a relentless growth of papillomas on the vocal cords, requiring repeated excisions to maintain an adequate airway. Because of its antiproliferative effects on epithelial tissues, 13-cis-retinoic acid (0.5-2.0 mg/kd/day p.o.) was used in five patients whose disease was poorly controlled by laser beam surgery. Control of disease for 24+, 5+, and 12 months has been achieved in three of the patients, with two complete and one partial responses. Side effects of treatment were mild and rapidly reversible, following a 25-50% reduction in drug dose.

Topics: Adult; Aged; Antineoplastic Agents; Child; Child, Preschool; Combined Modality Therapy; Drug Evaluation; Female; Humans; Isotretinoin; Laryngeal Neoplasms; Laser Therapy; Male; Middle Aged; Papilloma; Tretinoin

Tumor initiation in CD-1 mice by benzo[a]pyrene (BaP) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was unaffected by topical pretreatment with 13-cis-retinoic acid (13-cis-RA). Likewise, anthralin-induced tumor promotion in SENCAR mice was unaffected by pretreatment with 13-cis-RA. These results suggest that the action of retinoids in preventing either tumor initiation or promotion is very carcinogen or cocarcinogen specific.

Topics: Animals; Anthralin; Benzo(a)pyrene; Benzopyrenes; Female; Isotretinoin; Methylnitronitrosoguanidine; Mice; Papilloma; Skin Neoplasms; Time Factors; Tretinoin

Two retinoids (13-cis-retinoic acid and retinyl palmitate ) have been shown to exert a good preventive effect in chemically induced papillomas and carcinomas of the skin in female Swiss mice; this effect was investigated over a period of 23 weeks. The tumors were induced by repeated topical application of 3-methylcholanthrene (0.3% MCA, dissolved in acetone; 14 applications). Retinyl palmitate (RP; 6 mg in 0.1 ml acetone/mouse; 10 applications) and 13-cis-retinoic acid (RA; 3 mg in 0.1 ml acetone/mouse; 10 applications) were also administered topically for the 3rd to 9th week from the start of the experiment. This investigation gave evidence for the fact that both the retinoids did not only inhibit the development of skin papillomas but had also a marked effect on skin carcinomas.

Topics: Animals; Diterpenes; Isotretinoin; Methylcholanthrene; Mice; Papilloma; Retinyl Esters; Skin Neoplasms; Tretinoin; Vitamin A