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A small number of acylating agents are known to be carcinogenic. The structure-activity relationships and carcinogenicity (SARC) of these compounds are reviewed in this report. In addition, the results of chronic bioassays of three previously untested compounds are described. Female ICR/Ha Swiss mice, 30–50 per group, were used in all tests. The test duration was 18–22 months. Diethylcarbamyl chloride (DECC), ethyl chloroformate (ECF), and dichloroacetyl chloride (DCAC) were tested by repeated skin application, in two-stage carcinogenesis with phorbol myristate acetate (PMA) as promoter, and by repeated subcutaneous injection. Dimethylcarbamyl chloride was used as a positive control together with control groups. All three compounds showed marginally significant incidences of papillomas and carcinomas when tested as initiators. ECF and DCAC did not show skin tumorigenicity in the repeated skin application tests. DECC showed weak carcinogenicity compared to DMCC. Subcutaneous injection resulted in the same pattern of tumorigenicity. Thus, the four acylating agents showed the following decreasing order of carcinogenicity: DMCC > DECC > ECF ≅ DCAC. All four compounds hydrolyze rapidly in water, with the following decreasing order of rate of hydrolysis: DCAC > DMCC ECF ≅ DECC. Their mechanisms of hydrolysis are: DMCC, DECC, and DCAC, SN1; ECF, SN2. There is no clear correlation between rate or mechanism of hydrolysis and carcinogenicity of these acylating agents. [ABSTRACT FROM PUBLISHER]

The contribution of change over time in parent and child characteristics to parents' resolution of child's diagnosis was examined among 78 mothers and fathers of children with autism spectrum disorder. Children's characteristics (e.g., mental age and severity of symptoms), parental characteristics (e.g., attachment-related anxiety and stress level), and parents' resolution of their child's diagnosis (resolved vs. unresolved) were examined at Time 1, and reassessed 3 years later at Time 2. Results indicated a deferential contribution of change in parent and child characteristics among mothers and fathers. An increase in child symptom severity and in maternal attachment-related anxiety, as well as longer durations of time since receiving the diagnosis, significantly predicted maternal resolved status at Time 2. Conversely, none of the changes in children's or paternal characteristics predicted paternal resolved status at Time 2. Results are discussed in relation to child and parental contributions to resolution, the differences in the adjustment and well-being of mothers and fathers of children with autism spectrum disorder, parental growth following receiving the diagnosis, and the need for intervention components specific to parental resolution and attachment-related anxiety.

Parents of individuals with autism were examined using the Broad Autism Phenotype Questionnaire (BAPQ; Hurley et al. in J Autism Dev Disord 37:1679-1690, 2007) assessing BAP-related personality and language characteristics. The BAPQ was administered to parents as a self-report and as an informant (spouse)-based measure. Results indicated the same pattern of differences for the informant and best-estimate (average between self-report and informant scores) reports. Fathers were rated as more "aloof" than mothers, whereas mothers were rated as more "rigid" than fathers. Fathers described their wives as less "aloof" and more "rigid" compared to the mothers' self-descriptions. Correlational analyses revealed no significant associations among parent/child characteristics and parents' BAPQ scores. Results are discussed in reference to sex differences in BAP-related characteristics in parents of children with autism.

Siblings of probands with autism spectrum disorders are at higher risk for developing the broad autism phenotype (BAP). We compared the linguistic abilities (i.e., pragmatic language, school achievements, and underling reading processes) of 35 school-age siblings of children with autism (SIBS-A) to those of 42 siblings of children with typical development. Results indicated lower pragmatic abilities in a subgroup of SIBS-A identified with BAP related difficulties (SIBS-A-BAP) whereas school achievements and reading processes were intact. Furthermore, among SIBS-A-BAP, significant negative correlations emerged between the severity scores on the Autism Diagnostic Observation Schedule and full and verbal IQ scores. These results are discussed in the context of the developmental trajectories of SIBS-A and in relation to the BAP.

We studied demethylation within the transgene promoter in transgenic mice carrying the N-ras proto-oncogene driven by the mouse mammary tumor long terminal repeat (MMTV/N-rasN) and the relationship of demethylation to transgene overexpression and tumorigenesis. Demethylation at Fspl or Clal sites correlated with age of the animal and transgene expression in nontumorous mammary gland. Demethylation preceded expression in this tissue. In lymphomas and mammary tumors, the promoter Fspl and Clal sites were significantly more demethylated than in nontumorous control tissues. The Aval, Cfol, and Hpall sites were also found to be undermethylated in older animals and showed differences between tumor and control tissues. Two additional sites (Eagl and Narl) remained fully methylated in all tissues. In contrast with normal tissue, demethylation at the Fspl and Clal sites and expression were not correlated in tumor tissue. An increase in expression in normal tissue initially occurred and was correlated with the level of promoter demethylation; this increase was followed by a further increment in transgene expression when tumors developed. Thus, promoter demethylation leading to transgene overexpression was associated with long-latency tumorigenesis in MMTV/N-rasN transgenic mice. Demethylation of proto-oncogene promoters may therefore be a mechanism of carcinogenesis that requires further investigation in human tumors.

The induction of tumors with chemicals and the production of transgenic animals are two experimental approaches to study oncogene involvement in carcinogenesis. The combination of both strategies offers an excellent model system to study tumor development. This study analyzes the potential cooperation of N-methylnitrosourea (MNU) treatment and N-ras proto-oncogene overexpression in tumorigenesis in transgenic mice. The overexpression of the N-ras proto-oncogene in these animals is associated with development of mammary tumors and lymphomas. After MNU treatment we analyzed tumor incidence and latency, levels of transgene expression, and pattern of ras mutations in codons 12, 13, and 61 of H-, K-, and N-ras genes in both tumor types. Transgenic mice treated with MNU had significantly (P < 0.001) shorter latency of appearance of mammary tumors [8.6 +/- 3.0 (SD) months] than phosphate-buffered saline-treated transgenics (12.8 +/- 2.3 months). All mammary tumors overexpressed the N-ras transgene and lacked ras mutations. Moreover, MNU-treated transgenics had an incidence and latency of lymphomas similar to that of MNU-treated nontransgenic mice. No significant differences in incidence of point mutations (K-ras codon 12 or 13 and N-ras codon 61) in lymphomas were seen between these two groups. All lymphomas overexpressed the N-ras transgene, except for those carrying a K-ras point mutation. Overexpression of the N-ras proto-oncogene cooperates with non-ras genes mutated by MNU in mouse mammary carcinogenesis. Conversely, N-ras proto-oncogene overexpression does not show cooperation with MNU in lymphomagenesis in our system. This study suggests that proto-oncogene overexpression may be a mechanism of activation of the ras pathway, alternative to point mutation. Similarly to actions for ras genes activated by point mutation, overexpression of the N-ras protooncogene predisposes to tumorigenesis and cooperates with a carcinogen in tumorigenesis. The possibility that ras overexpression plays a role in human breast tumorigenesis requires active investigation.

We have produced transgenic mice that carry a foreign gene construct consisting of the N-ras proto-oncogene driven by the mouse mammary tumor virus (MMTV) long terminal repeat. Overexpression of the normal N-ras gene is associated with development of hyperplasias and tumors in a variety of tissues. The tumors are clearly malignant, as evidenced by the presence of metastatic lesions. Extensive analysis of the foreign ras gene in these tumors by use of polymerase chain reaction and sequencing demonstrates in all cases the absence of somatically acquired mutations at those codons normally associated with activation of the ras genes. Thus, these tumors develop from overexpression of the proto-oncogene rather than the presence of the mutated oncogene. These data demonstrate that overexpression of a protooncogene of the ras family can predispose cells in vivo to fully malignant behavior.

The conversion of a normal cell into a metastatic tumor is thought to occur in a stepwise progression of genetic changes that affect both growth control and interactions with the extracellular environment. The development of invasiveness allows tumor cells to escape from their primary site. We have investigated transgenic mice that develop both invasive intestinal neuroendocrine tumors and noninvasive tumors of the pancreatic beta-cells. Visual inspection and gene expression studies indicate that the beta-cell tumors rarely metastasize. In contrast, intestinal tumors that first appear in submucosal areas metastasize with high frequency to the lymph nodes and liver. No evidence of preneoplastic mucosal lesions was seen in the intestine, indicating that invasiveness is acquired early in the tumorigenic progression of these cells. Comparison of intestinal and pancreatic neuroendocrine tumors in transgenic mice suggests that an early requirement for invasiveness may contribute to metastatic potential.

Transgenic mice carrying the activated N-ras oncogene under the transcriptional control of the mouse mammary tumor virus (MMTV) long terminal repeat were produced. The transgene is expressed in a tissue distribution consistent with the fact that it is driven by the MMTV-LTR, and similarly to MMTV/H-ras constructs, its presence elicits tumors in Harderian, mammary and salivary glands. In addition it appears to compromise male reproductive function, which has not been described with the other ras transgenes. This finding is consistent with the existence of distinct physiological actions for each of the ras family members.

The direct-acting SN1 alkylating agent isopropyl methanesulfonate (IMS) was carcinogenic by subcutaneous injection in female Hsd:(ICR)BR mice, causing thymic lymphoid neoplasms within 7 months in at least 20 of 32 treated mice. No such neoplasms were observed in mice treated with the direct-acting SN2 methyl homolog, methyl methanesulfonate (MMS). Both the IMS-treated mice and the MMS-treated mice initially received 20 mumole of the respective compounds by sc injection once weekly; however, because of toxic effects the dose of IMS was reduced to 10 mumole per injection on the 63rd day and further reduced to 5 mumole per injection on the 120th day, after which this dose was maintained until the 202nd day when the last surviving IMS-treated mouse became moribund and was sacrificed. In 2 of the MMS-treated mice, 93% of which were alive at 288 days, tumors were observed at the site of injection, one being a papilloma and the other a subcutaneous sarcoma. IMS has not previously been implicated as a carcinogen, to our knowledge. Its induction of thymic lymphomas may conceivably be related to its ability to alkylate exocyclic oxygen atoms in the DNA of hemopoietic cells.

Chondrosarcoma arising in the nasal septum has been previously described only 11 times. In this report, another case occurring in an 89-year-old man is discussed. The rarity of such a tumor arising in previously normal cartilage is emphasized. Prognostic factors and surgical treatment are discussed.

Reaction of acrylic acid (AA) at pH 7.0 and 37 degrees C for 40 days with 2'-deoxyadenosine (dAdo), 2'-deoxycytidine (dCyd), 2'-deoxyguanosine (dGuo) and thymidine (dThd) resulted in the formation of 2-carboxyethyl (CE) adducts via Michael addition. The alkylated 2'-deoxynucleoside adducts isolated (percent yield after 40 days) were 1-CE-dAdo (5%), N6-CE-dAdo (11%) (via Dimroth rearrangement of 1-CE-dAdo), 3-CE-dCyd (7.5%), 7-CE-Gua (4%), 7,9-bis-CE-Gua (0.9%) (formed by reaction of AA with depurinated 7-CE-Gua during the course of the reaction) and 3-CE-dThd (0.5%). The products isolated following in vitro reaction of AA with calf thymus DNA at pH 7.0 and 37 degrees C for 40 days were (nmol/mg DNA) 1-CE-Ade (9.9), N6-CE-Ade (8.2), 7-CE-Gua (7.2) and 3-CE-Thy (1.9). Compound 3-CE-Cyt was not detected. Thus the adducts formed following in vitro reaction of AA with DNA are identical to those formed by in vitro reaction of the carcinogen beta-propiolactone (BPL) with DNA as reported in an earlier paper. Structures were assigned on the basis of identical UV spectra, Rf values on paper chromatograms and Rt values on HPLC as marker compounds prepared from reactions of BPL with 2'-deoxynucleosides and 2'-deoxynucleotides-5'-monophosphoric acids. AA was assayed for carcinogenic activity by s.c. injection (20 mumol, once a week for 52 weeks) in female Hsd: (ICR)Br mice. Two mice with sarcomas at the site of application were observed out of 30 mice. Malignancies were not observed in solvent and no-treatment controls. The bioassay results reported in this paper and elsewhere in the same strain of mice suggest that AA is a weak carcinogen in female Hsd:(ICR)Br mice.

4a alpha-Phorbol-9,9a-didecanoate, 4a alpha-phorbol-9-myristate-9a-acetate, and phorbol-9-myristate-9a-acetate-3-aldehyde were tested for skin tumor-promoting activity by using 7,12-dimethylbenz(a)anthracene as the initiating agent. There were 30 female ICR/Ha mice/group, and tests were continued for 434 to 461 days. 4a alpha-Phorbol-9,9a-didecanoate and 4a alpha-phorbol-9-myristate-9a-acetate were devoid of tumor-promoting activity. Phorbol-9-myristate-9a-acetate-3-aldehyde resulted in 10 mice with papillomas, 2 of which also bore squamous carcinomas of the skin. The positive control group, in which phorbol myristate acetate was used as promoting agent, resulted in 30 mice bearing multiple papillomas and 15 bearing squamous carcinomas of the skin. The effects of structural and stereochemical changes on tumor-promoting activity suggest that a primary interaction of the phorbol ester series is binding at specific sites on the plasma membrane.

The lining of a gastric duplication cyst was examined ultrastructurally and immunohistochemically. The cyst lining displayed the range of differentiation seen in normal fundic mucosa.

Two-stage carcinogenesis experiments on mouse skin (female ICR/Ha Swiss mice) were done by initiating mice at three age levels (6, 44, and 56 weeks) and promoting after a 2-week interval. In another series, mice were initiated at age 6 weeks, and three time intervals (2, 36, and 56 weeks) were used between initiation and promotion. The initiating agent was 7, 12-dimethylbenz(a)anthracene and the promoting agent was phorbol myristate acetate in all experiments. The results showed a general decrease in tumor production with increasing age at the time of promotion. However, the initiating effect persisted even when the interval between initiation and promotion was 56 weeks.

Four bifunctional and one trifunctional alpha-chloro ethers were tested for carcinogenicity. These compounds were bis-1,2-(chloromethoxy)ethane (Compound I), bis-1,4-(chloromethoxy)butane (Compound II), bis-1,6-(chloromethoxy) hexane (Compound III), bis-1,4-(chloromethoxy)-p-xylene (Compound IV), and tris-1,2,3-(chloromethoxy)propane (Compound V). trans-1,4-Dichlorobutene-2 (Compound VI) was tested along with the five alpha-chloro ethers. All six compounds were tested in female ICR/Ha Swiss mice for 502 to 569 days, depending on survival, by skin application or s.c. and i.p. injection. There were 30 or 50 mice/group. The i.p. and s.c. injections were given once weekly at 0.1 or 0.3 mg of compound dissolved in 0.05 ml tricaprylin for Compounds I to V and 0.05 mg/0.05 ml tricaprylin for Compound VI for the duration of the tests. The skin applications, three times weekly, were at doses of 0.3 or 1.0 mg/0.1 ml cyclohexane for the alpha-chloro ethers and 1.0 mg/0.1 ml acetone for Compound VI. Vehicle and no treatment controls were carried out together with the test compounds. Significance values (p) were calculated for all the compounds tested. Three compounds, I, IV and V, gave notable tumor incidences by all three routes of administration. Compounds II, III, and VI were either inactive by one or more routes of administration or gave low tumor yields.

Rat mammary gland explants placed in organ culture underwent intraductal hyperplasia in the presence of insulin. The hyperplasia reached its maximum at about 2 weeks of culture and exhibited several morphologic variations. By ultrastructural criteria, it was shown that the proliferating cell was derived from the epithelial rather than the myoepithelial component of the ductal lining cells. Testosterone, added at the beginning of the experiment, partially inhibited the hyperplastic process.

Six epoxides of structurally related chloroalkenes were examined for their carcinogenicity by chronic testing in female ICR/Ha Swiss mice, 30/group. Repeated skin application three times weekly or s.c. injection once weekly were used for the life spans of the mice. The epoxides were: cis-1-chloropropene oxide, trans-1-chloropropene oxide, cis-1,3-dichloropropene oxide, trans-1,3-dichloropropene oxide, trichloroethylene oxide (TCEO), and tetrachloroethylene oxide (PCEO). In mouse skin, cis-1-chloropropene oxide, trans-1-chloropropene oxide, cis-1-,3-dichloropropene oxide, and trans-1,3-dichloropropene oxide induced statistically significant incidences of squamous carcinomas of the skin; TCEO did not cause any skin tumors; and PCEO resulted in three mice with benign skin tumors and one with a squamous carcinoma of the skin. Repeated s.c. injection of the four propene oxides induced statistically significant incidences of local tumors, mostly fibrosarcomas. This was not the case with TCEO and PCEO. The data are consistent with the carcinogenicity findings on the parent chloropropenes and suggest that the epoxides function as their activated carcinogenic intermediates. The essentially negative findings with TCEO and PCEO suggest further studies on the carcinogenicity of trichloroethylene and tetrachloroethylene.

The goal of these experiments in female Hsd:(ICR)Br mice was to determine whether the direct-acting SN1 alkylating carcinogen isopropyl methanesulfonate (IMS) is carcinogenic and to compare its effects with those of the direct-acting SN2 methyl homologue, methyl methanesulfonate (MMS). The compounds were administered by topical application and s.c. injection. Analysis at the 288th day of mice receiving s.c. injections of IMS and MMS was the subject of a previous report (A. Segal et al., Proc. Soc. Exp. Biol. Med., 183: 132-135, 1986). The s.c. and topical application experiments were terminated at the 450th day and the final results are reported in this paper. In mice treated by s.c. injection with IMS, thymic lymphomas were observed in at least 20 of 32 mice, the first at the 40th day, and neoplasms were not observed at the injection site. Of the 30 MMS-treated mice, 11 developed sarcomas at the injection site and one thymic lymphoma was observed. In mice treated topically with IMS, thymic lymphomas were observed in 20 of 30 treated mice, the first at the 102nd day, and squamous cell carcinomas at the injection site were observed in 9 mice. Neither squamous cell carcinomas nor thymic lymphomas were observed in 30 mice following topical application of MMS. The direct-acting SN2 aklylating carcinogen beta-propiolactone was also administered by topical application. At the 450th day, at the same dose used for MMS (40 mumol/application), papillomas of the skin were observed in 25 of 30 treated mice, squamous cell carcinomas of the skin were seen in 17 mice, and one thymic lymphoma was observed. The results suggest that the rapid induction of thymomas by IMS may be related to its ability to alkylate exocyclic oxygen atoms in DNA of hemopoietic cells and also to a sensitivity of these cells to such lesions.

Irreversible pulmonary interstitial fibrosis developed 36 days after a single course of BCNU (total, 400 mg) in a patient with a malignant brain tumor. The case is unique in that irreversible changes developed shortly after a single course of BCNU whereas heretofore such permanent changes have been associated only with multiple courses of the drug (2,000-4,000 mg). This suggests that individual differences in the local sensitivity of lung tissue may be as important as the dose of the drug in determining whether irreversible fibrosis will develop.

Primary carcinoma of breast was treated in 967 patients from 1962 through 1972. Thirty-five of these patients had a second primary tumor of which 50% were discovered simultaneously. A family history for cancer was recorded in 26% of the patients with bilateral cancer. Patients found their tumor more often than the physician except in the simultaneous cases where the physician was more successful. Pathological examination showed 10% of the tumors were comedo, lobular carcinoma in situ, papillary, or tubular cancers. In the metachronous group, 50% of the axillae were involved on both sides. In the simultaneous cases the axilla was less frequently involved. Mammography, biopsies of the second breast, and prophylactic mastectomy in certain high-risk patients should improve survival rates.