Papilloma Growth Research Articles

Enhanced growth of primary tumors in cancer-prone mice after immunization against the mutant region of an inherited oncoprotein.

One major objective of tumor immunologists is to prevent cancer development in individuals at high risk. (TG.AC x C57BL/6)F1 mice serve as a model for testing the feasibility of this objective. The mice carry in the germline a mutant ras oncogene that has an arginine at codon 12 instead of glycine present in the wild-type, and after physical (wounding) or chemical promotion, these mice have a high probability for developing papillomas that progress to cancer. Furthermore, F1 mice immunized with Arg(12) mutant ras peptide in complete Freund's adjuvant (CFA) develop T cells within 10 d that proliferate in vitro on stimulation with the Arg(12) mutant ras peptide. Within 14 d, these mice have delayed-type hypersensitivity to the peptide. Immunization with CFA alone or with a different Arg(12) mutant ras peptide in CFA induced neither response. To determine the effect of immunization on development of tumors, mice immunized 3 wk earlier were painted on the back with phorbol 12-myristate 13-acetate every 3 d for 8 wk. The time of appearance and the number of papillomas were about the same in immunized and control mice, but the tumors grew faster and became much larger in the mice immunized with the Arg(12) mutant ras peptide. Thus, the immunization failed to protect against growth of papillomas. The peptide-induced CD4(+) T cells preferentially recognized the peptide but not the native mutant ras protein. On the other hand, mice immunized with Arg(12) mutant ras peptide and bearing papillomas had serum antibodies that did bind native mutant ras protein. Together, these studies indicate that active immunization of cancer-prone individuals may result in immune responses that fail to eradicate mutant oncogene-expressing tumor cells, but rather induce a remarkable enhancement of tumor growth.

The inhibitory effects of bryostatin 1 administration on the growth of rabbit papillomas

Bryostatin 1 is a protein kinase C modulator that shows antineoplastic activity in a variety of tumor systems. This study examined the effects of bryostatin 1 administration on papilloma growth in rabbits. Investigations of optimal route, dose, and schedule were performed. Several groups of rabbits were inoculated with cottontail rabbit papillomavirus (CRPV) DNA. Bryostatin 1 was administered i.v., both daily and weekly, and intralesionally both weekly and bi-weekly. Intralesionally dosed papillomas were examined histologically for immune cell infiltration. In weekly and daily i.v. trials, 2.5 and 1.0 μg/kg, respectively, showed the greatest overall reduction in tumor size. Bryostatin 1 administered intralesionally also slowed papilloma growth. Treated lesions had significantly higher numbers of heterophils and eosinophils.

Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis

OBJECTIVE: We report the preliminary results of a phase I trial using indole-3-carbinol for the treatment of recurrent respiratory papillomatosis. Indole-3-carbinol is a chemical that is found in high concentrations in cruciferous vegetables and has been shown to alter the growth pattern of recurrent respiratory papillomatosis cell cultures and to be effective in an in vivo animal model of recurrent respiratory papillomatosis. METHODS: Eighteen patients were treated with oral indole-3-carbinol and had a minimum follow-up of 8 months and a mean follow-up of 14.6 months. All patients received indole-3-carbinol, and outcome measures included a change in papilloma growth rate and the need for surgery during treatment compared with before treatment. All patients had serial examinations with videoendoscopy to document papilloma location and growth rate. RESULTS: Thirty-three percent (6 of 18) of the study patients had a cessation of their papilloma growth and have not required surgery since the start of the study. Six patients have had reduced papilloma growth rate, and 6 (33%) patients have shown no clinical response to indole-3-carbinol. Indole-3-carbinol affects the ratio of hydroxylation of estradiol; changes in the ratios of urinary 2-hydroxylation and 16-hydroxylation of estradiol caused by indole-3-carbinol correlated well with clinical response. No major complications or changes in the children’s growth curve were noted. CONCLUSIONS: The preliminary results of treating recurrent respiratory papillomatosis with indole-3-carbinol holds promise. Longer follow-up of this patient group and a blinded, controlled trial are required. We conclude that indole-3-carbinol appears to be safe and well tolerated and may be an efficacious treatment for recurrent respiratory papillomatosis. (Otolaryngol Head Neck Surg 1998;118:810-5.)

Inhibitory effect of black tea on the growth of established skin tumors in mice: effects on tumor size, apoptosis, mitosis and bromodeoxyuridine incorporation into DNA.

Female CD-1 mice were initiated with a single topical application of 7,12-dimethylbenz[a]anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate. Mice with established papillomas were then treated with black tea or decaffeinated black tea (approximately 4 mg tea solids/ml) as the sole source of drinking fluid for 11-15 weeks. In four separate experiments, oral administration of black tea inhibited the growth of papillomas (increase in tumor volume/mouse) by an average of 35%, 37%, 41% and 48%, respectively. Studies with decaffeinated black tea gave inconsistent results. In one experiment, administration of decaffeinated black tea inhibited papilloma growth (increase in tumor volume/mouse) by 27%, but in two additional experiments papilloma growth was stimulated by 14% and 193%, respectively. In a separate experiment, skin tumors were generated by treating SKH-1 female mice with ultraviolet B light (UVB; 30 mJ/cm2) twice weekly for 22 weeks, after which UVB administration was stopped. Tumors were allowed to develop during the following 13 weeks, and tumor-bearing mice were then treated with black tea (6 mg/ml tea solids) as the drinking fluid for 11 weeks. In this experiment, tumor growth (increase in tumor volume/mouse) was inhibited by 70%. Histological examination revealed that tea-treated mice had a 58% decrease in the number of nonmalignant tumors (primarily keratoacanthomas)/mouse and a 54% decrease in the number of squamous cell carcinomas/mouse. In addition, administration of black tea decreased the volume per tumor by 60% for nonmalignant tumors and by 84% for carcinomas. Mechanistic studies with tumors from these mice revealed that administration of black tea decreased the bromodeoxyuridine labeling index in squamous cell papillomas, keratoacanthomas and squamous cell carcinomas by 56%, 45% and 35%, respectively, and the apoptosis index was increased by 44%, 100% and 95%, respectively. Administration of black tea decreased the mitotic index in keratoacanthomas and squamous cell carcinomas by 42% and 16%, respectively. The results indicate that oral administration of black tea to tumor-bearing mice inhibited proliferation and enhanced apoptosis in nonmalignant and malignant skin tumors.

Transplantation analyses of the immunogenicity of epidermal tumors generated in murine skin two-stage carcinogenesis protocols.

SSIN mice are very sensitive to tumor promoters in two-stage skin carcinogenesis protocols. It was recently reported that SSIN mice have fewer CD8+ T-cells than other strains of mice and develop a weaker cytotoxic T-cell response upon challenge with an allogeneic tumor transplant. The significance of this muted immune response to processes involved in two-stage carcinogenesis depends on the immunogenicity of the tumors generated in such protocols. Although they have low CD8+ T-cell contents, SSIN rejected a variety of subcutaneously transplanted allogeneic murine tumors. Analyses of the growth of primary papillomas derived from 7,12-dimethylbenz[a]anthracene-initiated/12-O-tetradecanoylphorbol-13-ac etate-promoted SSIN mice and then subcutaneously transplanted into triple-deficient (bg-nu-xid), athymic nude and immune-competent and immunosuppressed SSIN mice revealed that few tumors took and tumor takes were not markedly influenced by the immumological status of the transplant recipient. Two tumor cell lines (RS1 and RS2) were derived from the transplantation studies and could be passaged in normal SSIN mice (H-2q haplotype). Both tumors were squamous cell carcinomas (SCCs) by the second in vivo passage and were rejected in allogeneic mice (BALB/c) but grew in FVB/N mice, a strain having the H-2q haplotype. Transplantation studies revealed that prior exposure to RS1 and RS2 did not prime SSIN mice to reject a subsequent tumor challenge. Three primary SCC tumors derived from SSIN mice in a two-stage carcinogenesis protocol also grew when subcutaneously transplanted in SSIN mice and could be serially passaged. Consequently, the epidermal SCCs that develop in two-stage carcinogenesis protocols appear to be nonimmunogenic.

Gene expression and cellular sources of inducible nitric oxide synthase during tumor promotion.

The present studies examined the temporal sequence of inducible nitric oxide synthase (iNOS) gene expression and the cellular sources of iNOS protein and of 3-nitrotyrosine, as a marker of production of nitric oxide-derived reactive nitrogen intermediates during murine multi-stage carcinogenesis. Levels of iNOS mRNA in dorsal skin isolated from acetone-treated female Sencar mice were 2.5-fold higher than iNOS gene expression detected in cutaneous tissue isolated from Sencar mice at 1, 3, 6, 10, 16 and 22 weeks after exposure to a single topical application of 25 nmol 7,12-dimethylbenz[a]anthracene (DMBA) followed by repetitive applications of 2 microgram 17-O-tetradecanoylphorbol-13-acetate (TPA). Papillomas isolated at 16 and 22 weeks of a tumor promotion protocol also had low levels of iNOS mRNA. The diminished levels of iNOS mRNA inversely correlated with the extent of TPA-induced epidermal hyperplasia. In acetone-treated mouse skin, iNOS immunospecific antibody binding was localized to the stratum corneum and suprabasal keratinocytes. In contrast, iNOS protein was present in lower amounts and was localized to the upper-most suprabasal keratinocytes in cutaneous tissue isolated at 22 weeks following a single exposure to either 25 nmol DMBA or acetone and repetitive applications of 2 microgram TPA. At all time points examined over the 22 week time period of papilloma growth, infiltrating neutrophils within the dermis bound significant levels of anti-iNOS antibodies. The production of iNOS by neutrophils within the dermis correlated with the formation of protein nitrotyrosination within the dermal tissue, as detected by 3-nitrotyrosine-specific antibodies. The present studies indicate that NOS and reactive nitrogen intermediates, including peroxynitrite, are produced specifically by dermal neutrophils during the tumor promotion process at time points that correspond to simultaneous production of reactive oxygen intermediates. Conversely, iNOS is simultaneously down-regulated in hyperplastic epidermis and in papillomas.

Constitutive expression of B7-1 (CD80) on mouse keratinocytes does not prevent development of chemically induced skin papillomas and carcinomas.

Expression of the B7-1 (CD80) costimulatory molecule in a variety of tumor cell lines leads to an enhanced CD8+ T cell response to tumor Ags. We used transgenic mice constitutively expressing B7-1 on keratinocytes (K14/B7-1 line) to determine whether keratinocyte B7-1 expression would inhibit the development of papillomas and carcinomas following two-stage chemical carcinogenesis in skin. FVB inbred mice carrying the K14/B7-1 transgene and controls were initiated with 25 micrograms of 7,12-dimethylbenz[a]anthracene and promoted weekly with 5 micrograms of 12-O-tetradecanoylphorbol-13-acetate for 20 wk. Expression of the B7-1 transgene did not result in statistically significant decreases in the mean number of papillomas or carcinomas compared with controls. The incidence of carcinomas in both transgenic and control mice reached 90% or greater by 60 wk after initiation. Carcinoma cell lines established from the K14/B7-1 mice maintained expression of B7-1 and Kq. These B7-1 expressing carcinomas grew progressively following intradermal injection into syngeneic FVB mice, further demonstrating their inability to evoke protective tumor immunity. These same carcinoma cell lines were rapidly rejected by minor alloantigen-mismatched SWR mice, confirming their susceptibility to immune effector mechanisms. The failure of constitutive B7-1 expression on keratinocytes to prevent the growth of squamous cell papillomas and carcinomas may reflect the limited immunogenicity of tumors arising after initiation-promotion carcinogenesis. Our results in this transgenic model system are further evidence that B7-1 gene therapy alone may not be sufficient to induce protective immunity to some types of tumors.

Inhibition of pro-inflammatory cytokine gene expression and papilloma growth during murine multistage carcinogenesis by pentoxifylline.

Topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to the dorsal epidermis of Sencar mice induces synthesis of pro-inflammatory cytokines, including interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha). These proteins differentially regulate proliferation of epidermal keratinocytes, as well as stimulate chemotaxis, migration and production of reactive oxygen and nitrogen intermediates by leukocytes. Studies over the past several years have demonstrated that pentoxifylline ([1-(5-oxohexyl)-3,7-dimethyl-xanthine], oxpentifylline), which is a methylxanthine derivative used clinically for treatment of vascular insufficiency, has the unique ability to inhibit synthesis of pro-inflammatory cytokines. The present studies were performed to examine the effects of acute and chronic administration of pentoxifylline on TPA-induced cutaneous inflammation in female Sencar mice treated once with 10 micrograms TPA and also to determine the ability of pentoxifylline to inhibit the tumor promotion process in mice treated with a single application of 25 nmol 7,12-dimethylbenz[a]anthracene (DMBA) followed for 8 weeks by twice weekly topical application of TPA. Intraperitoneal injection of 50 micrograms/g pentoxifylline at 30 min prior to topical application of 10 micrograms TPA to the dorsal epidermis of Sencar mice inhibited TPA-induced IL-1 alpha and TNF-alpha gene expression 24 h after TPA treatment. Administration of pentoxifylline also significantly inhibited all parameters of acute TPA-induced inflammatory response examined 24 h later, including skin thickening (P < 0.005), infiltration of neutrophils into the dermis (P < 0.001), the corresponding dermal myeloperoxidase activity (P < 0.01) and epidermal hyperplasia (P < 0.001). Injection of 50 micrograms/g pentoxifylline over an 8 week time period significantly inhibited DMBA/TPA-induced papilloma growth (P < 0.05). These results indicate that administration of pentoxifylline is an effective means of inhibiting acute TPA-induced cutaneous inflammation and pro-inflammatory cytokine gene expression, as well as is effective as an antipromoter that inhibits papilloma growth.

Regression and progression characteristics of papillomas induced by chrysarobin in SENCAR mice.

The present study was designed to test the effects of a free radical generating tumor promoter, chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone), on the growth and progression of papillomas generated in the skin of SENCAR mice. In the first set of experiments, papillomas were generated by initiation with 6.4 microg of 7,12-dimethylbenz[a]anthracene (DMBA) followed by promotion with once-weekly applications of 52.8 microg chrysarobin for 10 weeks. The fate of individual papillomas was then monitored for a 20 week interval following cessation of promoter treatment. Five weeks after the cessation of chrysarobin treatment, the papilloma response reached a maximum of 13.2 papillomas/mouse. By the end of the 20 week interval 19% and 18% of the papillomas had regressed or coalesced respectively. A three-stage treatment protocol was also utilized to test the ability of chrysarobin to enhance the progression of pre-existing papillomas to squamous cell carcinomas (SCCs). In stage I, mice were initiated with 0.5 microg of DMBA. In stage II, mice were promoted with twice-weekly applications of 1 or 2 microg of 12-0-tetradecanoylphorbol-13-acetate (TPA) for 15 weeks. Then, in stage III, mice were treated with acetone, TPA (1 or 2 microg), chrysarobin (52.8 microg) or benzoyl peroxide (BzPo; 20 mg) for the next 45 weeks. The mean number of papillomas per mouse at plateau was very similar for all groups. The carcinoma incidence was also similar for all groups regardless of the treatment protocol used, as was the mean number of carcinomas per mouse. The ratio of papillomas that converted to SCCs in mice treated with chrysarobin during stage III was not significantly different from the acetone controls or any of the other treatment groups (P > 0.05, Kruskal-Wallis analysis). In addition, BzPo did not enhance the progression of papillomas to SCCs under the current experimental conditions. Collectively, the results indicate that papillomas promoted by chrysarobin have growth properties similar to those promoted by TPA under similar experimental conditions. Furthermore, despite its ability to generate free radical intermediates, chrysarobin does not enhance the malignant progression of pre-existing papillomas induced by TPA treatment.

Suppression of mouse skin papilloma by canthaxanthin and beta-carotene in vivo: possibility of the regression of tumorigenesis by carotenoids without conversion to retinoic acid.

Using mouse skin papilloma as a model system, we examined whether the antitumorigenic activity of carotenoids was related to their provitamin A activity. Oral administration of canthaxanthin (CX) or beta-carotene at 200 mg/kg/day for 14 days significantly reduced the cumulative size of papillomas induced on the skin by 9,10-dimethyl-1,2-benzanthracene (p < 0.05), after the accumulation of these carotenoids in the tumors. The levels of a protooncogene, c-myc, were simultaneously suppressed in papillomas in carotenoid-treated mice. Because CX cannot be converted metabolically to retinoids, these results suggested that CX directly inhibited the growth of papillomas. Neither the accumulation of retinoids nor the expression of a retinoic acid-inducible gene, retinoic acid receptor-beta, was found in papillomas of CX- and beta-carotene-treated mice, suggesting that, like CX, beta-carotene might exert the tumor-suppressing effect without being converted to retinoids. Thus a certain antitumorigenic activity of carotenoids appears not necessarily to require their provitamin A activity.

Saffron Chemoprevention in Biology and Medicine: A Review

A growing body of evidence indicate that carotenoids possess anticarcinogenic, anti-mutagenic and immunomodulating effects. Saffron obtained from the dried stigmas of Crocus sativus L., is an important spice, rich in carotenoids, consumed commonly in different parts of the world. Our laboratory first reported the anticancer activity of saffron extract (dimethyl-crocetin) against a wide spectrum of murine tumors and human leukemia cell lines. The present report reviews the role of saffron in serving as a chemopreventive agent in modifying cancer risk. Dose-dependent cytotoxic effect to carcinoma, sarcoma and leukemia cells in vitro were noted. Saffron delayed ascites tumor growth and increased the life span of the treated mice compared to untreated controls by 45-120%. In addition, it delayed the onset of papilloma growth, decreased incidence of squamous cell carcinoma and soft tissue sarcoma in treated mice. Understanding the mechanisms of action of saffron have been solitarily based on their carotenoid-like action. Our results indicated significant inhibition in the synthesis of nucleic acids but not protein synthesis. It appears now that saffron (dimethyl-crocetin) disrupts DNA-protein interactions e.g. topoisomerases II, important for cellular DNA synthesis.

Variable Light-Dose Effect on Photodynamic Therapy for Laryngeal Papillomas

We investigated photodynamic therapy (PDT) as an alternative treatment modality for recurrent respiratory papillomatosis. To optimize the effect of PDT, the light dose in this study was increased from 50 to 80 J/cm2. The clinical effect of these two light doses will be discussed and compared. Each patient's response was based on the growth rate of their papilloma before and after PDT. Disease response following 50 J/cm2 was compared with that after 80 J/cm2. The two study groups were also compared with a control group. Each patient received the dihematoporphyrin ether as an outpatient and underwent direct laryngoscopy and PDT at our institution. Twenty-eight patients (16 male and 12 female) with moderate to severe laryngeal disease and an age range of 18 months to 80 years were treated with a light dose of 80 J/cm2, 11 of those had been previously treated with 50 J/cm2. Seven patients had undergone photoactivation to the trachea. Twenty-four hours prior to photoactivation, patients received 2.5 mg/kg of dihematoporphyrin ether intravenously. Photodynamic therapy was given using an argon pump dye laser system. Reduction in disease severity greater than that achieved with 50 J/cm2. For patients treated initially with 80 J/cm2, the mean rate of papilloma growth decreased by approximately 50%, the same response seen with 50 J/cm2 of treatment. No additional benefit was found for those patients initially activated at 50 J/cm2 and then re-treated at 80 J/cm2. Although PDT has a beneficial effect on laryngeal papilloma growth rate, no significant change in response was obtained by increasing the light dose from 50 to 80 J/cm2.

Suppression by kampo medicine, sho-saiko-to, on papillomas induced by 7,12-dimethylbenz(a)anthracene in mice.

Sho-saiko-to (SST) is a Japanese modified, traditional Chinese herbal medicine (Kampo medicine) consisting of seven medical plants. We examined the effects of SST on formation and growth of squamous cell papillomas induced by 7,12-dimethylbenz(a)anthracene application in mouse skin. Chronic oral administration of SST reduced the incidence and growth of papillomas with the reduction of activities of succinate-dehydrogenase and thymidylate synthetase, which were evaluated as the cell viability and DNA synthesis via the de novo pathway, respectively.

Further studies on the influence of initiation dose on papilloma growth and progression during two-stage carcinogenesis in SENCAR mice.

The present study was designed to further evaluate the growth and progression of papillomas to squamous cell carcinomas (SCCs) in groups of animals receiving initiating doses of 7,12-dimethylbenz[a]anthracene (DMBA) producing relatively low papilloma yields following long term promotion (60 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA). For comparison, groups of animals were initiated with various doses of DMBA and then promoted with mezerein (MEZ), benzoyl peroxide (BzPo) and chrysarobin (CHRY). Following initiation, groups of female SENCAR mice received the following promoter doses: TPA (1.0 or 2.0 micrograms per mouse); MEZ (2.0 micrograms per mouse); BzPo (20.0 mg per mouse); and CHRY (52.8 micrograms per mouse). The maximum papilloma to SCC conversion ratio obtained with TPA in the current study was 0.32. This value was in the range of maximum conversion ratios obtained with the other compounds: MEZ, 0.40; CHRY, 0.32 and BzPo, 0.19. In general, the highest papilloma to SCC conversion ratios observed with TPA as the promoter were obtained in groups that received the lowest doses of DMBA and had relatively low papilloma burdens. A comparison of papilloma to SCC conversion in groups of mice promoted with TPA, MEZ or CHRY and having similar papilloma yields, revealed very similar conversion ratios. Comparison of the BzPo group with a similar papilloma yield indicated that the conversion ratio was slightly lower with this promoter. The present results indicate that in mice promoted with TPA and having relatively low papilloma numbers, a larger proportion of these papillomas progress to SCCs during continued promoter treatment. Furthermore, the results suggest that papillomas behave similarly in their ability to progress to SCCs regardless of the promoter used when comparing groups of mice with similar tumor numbers. The data are discussed in terms of possible mechanisms for the observed results.

Multiple mechanisms: the example of vitamin A.

It has become evident that retinoids control differentiation, embryonal development, and tumorigenesis. In animal models, skin tumorigenesis has been shown to be prevented by retinoids, which in this organ function as antitumor promoters in the two-stage system using 7,12-dimethylbenz(a)anthracene (DMBA) as the initiator, and 12-tetradecanoyl-phorbol-13-acetate (TPA) as tumor promoter. Even though pharmacological doses applied topically appear to inhibit tumor formation, we found that papilloma and keratoacanthoma growth required physiological concentrations of retinoic acid and that vitamin A deficiency was even more effective than excess retinoid in inhibiting SENCAR mouse skin tumorigenesis. In human beings, oral administration of retinoic acid after tumor resection was effective in inhibiting the appearance of new tumors on the skin of four patients with Xeroderma Pigmentosum, and was effective in preventing new primary tumor formations in patients treated for head and neck cancer. The newly-discovered nuclear receptors for retinoic acid function as transcriptional activators for several genes. In patients with acute promyelocytic leukemia presenting with a reciprocal translocation of chromosome 17 to chromosome 15, the breakpoint has been identified in the retinoic acid receptor alpha gene, which forms a fusion gene with a new gene termed myl, on chromosome 15. Treatment of the patients with retinoic acid causes complete remission of the APL. It also appears to generate cells that do not bear the translocation. Therefore, retinoids may well function as modulators of carcinogenesis both at the promotion level as well as by causing differentiation of neoplastically transformed cells.

Preclinical System for Evaluating Topical Podofilox Treatment of Papillomas: Dose-Response and Duration of Growth Prior to Treatment

The objective of the present study was to assess the utility of Shope rabbit papillomas as an animal model system for studying topical podofilox treatment and to evaluate dose-response relations and influence of duration of papilloma growth prior to treatment. New Zealand White rabbits received inoculations of cottontail rabbit papillomavirus (CRPV) virions of two dilutions at four sites total on the dorsum. Two papillomas on the left side were treated with podofilox (Oclassen Pharmaceuticals, Inc., San Rafael, CA). The drug was given topically twice each day, 5 d per week, for 21 d. We evaluated the effects of drug dose and the duration of papilloma growth prior to treatment. Results indicated that treatment beginning on day 28 with both 0.5 and 2.5% (w/v) podofilox inhibited papilloma growth, but 5.0% was more effective. In a separate experiment, papillomas were treated at 7, 21, or 60 d after virus inoculation. At 7 d, the untreated lesions were latent (not visible). At 21 d after infection, they were about 2.5 mm in diameter. At 60 d, papillomas were about 25 mm. Treatment with 5.0% podofilox beginning on any of those days strongly inhibited papilloma growth. Neither Southern blots nor PCR detected CRPV DNA in cured sites of previous virus infection. Antibody production to CRPV virion was not affected by drug treatment. 5.0% podofilox irritated normal skin adjacent to papillomas as evidenced by inflammation, induration, and superficial erosion. However, healing was satisfactory and no scarring resulted. We concluded that the Shope papilloma was a good model system for studying podofilox treatment because the lesions responded to drug across a broad range of drug concentrations and papilloma sizes.

Laryngeal papillomas in infants and children: Relationship to maternal venereal warts

A variety of studies has been directed at establishing the association between human papillomavirus (HPV), as manifested in the adult as a sexually transmitted disease, and laryngeal papillomas found in infants and children. In spite of substantial evidence for the transmission of HPV from women to their infants during childbirth, this association remains unknown to most clinicians in the specialty areas of childbearing and pediatrics. Nurse-midwives find evidence of venereal warts in 1% to 35% (1) of their pregnant clients, depending upon the subpopulation under consideration. A potential sequela of this common gynecologic finding is the growth of papillomas in the larynx of infants who are born to these women. Such growths are not immediately apparent and may be quite difficult to diagnose when they usually become symptomatic, between the ages of two and five years. Clinical symptoms are similar to pediatric findings in croup, asthma, and common upper airway infections. Education of both clinicians and patients regarding potential risks to progeny of infected adults will serve to guide diagnostic attempts in the pediatric population.

Effects of β-carotene on chemically-induced skin tumors in HRASkh hairless mice

In order to evaluate the role of beta-carotene as an inhibitor of skin carcinogenesis, hairless female HRA/Skh mice were treated with the initiator 7,12-dimethylbenz[a]anthracene (DMBA) and with the promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), and were fed a balanced diet free from vitamin A either with or without gavage-administered beta-carotene. There was no evidence of avitaminosis A or differences in body weight in mice deprived of beta-carotene and vitamin A, compared with those given 290 or 1430 IU beta-carotene/kg per day. Mice fed with normal animal feed pellets displayed a significantly higher body weight (28.5 +/- 1.95 g) compared with mice on the special diet (25.7 +/- 1.9 g), and also displayed a higher papilloma yield. However animals on the special diet, fed with beta-carotene from weaning, displayed significantly lower numbers of papillomas per mouse. This lower papilloma yield was evident particularly between 12-24 weeks after commencement of the study, which coincided with the period of maximum tumor yield in DMBA/TPA-treated mice. The characteristic regression of papillomas after that time points to the reversibility of many earlier papillomas, and their dependence on continued TPA administration. Evaluation of carcinomas in mice on the various dietary regimes showed there was no significant difference between any group, including those fed with beta-carotene continuously from weaning. The present results demonstrate that a sustained dietary intake of beta-carotene from 3 weeks of age partially suppressed the growth of papillomas, but did not affect the course of malignant progression in DMBA/TPA-treated HRA/Skh mice. It is evident that beta-carotene predominantly affects TPA-dependent papillomas, which possess reversible properties and have a low probability of progression to form carcinomas.

Acceleration of papilloma growth in mice fed high‐fat diets during promotion of two‐stage skin carcinogenesis

The effect of feeding a high-fat diet during the promotion phase of skin tumorigenesis was assessed in SENCAR mice. Tumors were initiated on the backs of mice by application of 10 nmol 7,12-dimethylbenz[a]anthracene (DMBA); the tumors were then promoted beginning one week later with twice weekly treatments of 2 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) each in 0.2 ml acetone. Control diet containing 5% corn oil was fed from four weeks before until one week after DMBA treatment in all groups. A high-fat diet (24.6% corn oil) was fed from one week after DMBA treatment; the other groups continued on the control diet. Mice were fed ad libitum, and those given the high-fat diet consumed more calories early in the study than the controls did. Treatment with TPA increased calorie consumption throughout the study. Body weights were elevated in mice fed high-fat diets and reduced by TPA treatment. The average number of papillomas per mouse did not differ between the low- and high-fat groups, but papillomas grew more rapidly on the mice fed a high-fat diet than those fed a low-fat diet. The feeding of a high-fat diet following DMBA treatment, in the absence of TPA administration, did not result in promotion of skin tumors. Therefore, a high-fat diet acted as a copromoter of skin tumors in SENCAR mice.

Clinical effects of alpha-interferon dose variation on laryngeal papillomas.

Achieving optimal clinical control of recurrent respiratory papillomatosis with prolonged treatment with human leukocyte (alpha) interferon appears to be dose-related and often requires individualized dosage elevation. Six of eight patients in this study needed a maximum dose of 18 x 10(6) IU/week for part of the therapy period to achieve better disease control. The strong correlation found between dosage and response suggests that it is the interferon causing the effect on disease expression, not just the unpredictable nature of the disease. An effect on papilloma growth was observed in all patients during IFN therapy. Three patients were able to be tapered off IFN with only minimal recurrence seen in one patient. No toxic side effects were observed.