Anal cancer incidence: genital warts, anal fissure or fistula, hemorrhoids, and smoking.

We conducted a study of 126 patients with anal and rectal squamous cell carcinoma and 372 randomly selected control subjects in the San Francisco Bay Area (CA) to test the hypothesis that these tumors are related to a history of anal intercourse, the presence of sexually transmitted diseases and other conditions of the anal area, treatment of these diseases or conditions, and history of use of cigarettes or other substances. The relative risk (RR) of cancer was elevated for men with a history of homosexual activity (RR = 12.4, P less than .001). However, after adjustment for other risk factors, this risk was reduced to 2.7 (P = .28). Risk was elevated for homosexual male patients who reported a history of genital warts (RR = 12.6, P = .03), anal fissure or fistula (RR = 9.1, P = .05), and cigarette smoking (RR = 1.9 for 20 pack-yr, P less than .001; RR = 5.2 for 50 pack-yr, P less than .001). (Pack-year is a unit of cigarette use equal to 365 packs.) There was also elevated risk for heterosexual male and female patients who reported a history of genital warts (RR = 4.4, P = .003), anal fissure or fistula (RR = 2.4, P = .03), and more than 12 episodes of hemorrhoids (RR = 2.6, P less than .001). These findings suggest that anal cancer risk is etiologically related to human papillomaviruses that cause genital warts. In addition, constant irritation, chronic inflammatory changes, and repeated epithelial regeneration that accompany noninfectious conditions may be related to risk of anal cancer. The higher risk among homosexual men is related to the higher prevalence of anal cancer risk factors for this group.

Uveal melanoma, hormonal and reproductive factors in women.

In a case-control study, we explored a potential association between uveal melanoma and reproductive factors in women. Responses from telephone interviews of 186 women diagnosed with uveal melanoma were compared with responses of 423 women without this disease. All women resided in 11 U.S. western states. We observed a decreased risk of uveal melanoma for women who had ever been pregnant [relative risk (RR) = 0.60, 95% confidence interval (CI) = 0.37 -0.95], with an increase in this protective effect with more live births after adjustment for age, menopausal status, eye color, and skin sensitivity to the sun (1-2 births, RR = 0.47,95% CI 0.29-0.78; 3-4 births, RR = 0.38, 95% CI = 0.22-0.64; 5 or more births, RR = 0.33, 95% CI = 0.15-0.71). The largest effect was observed between nulliparous and parous women. No other reproductive factors, including use of oral contraceptives or postmenopausal estrogens, were shown to be related to risk for uveal melanoma. We conclude that most reproductive factors in this population play little or no role in the etiology of uveal melanoma. The association with number of live births must be confirmed in other studies to assure that it is unrelated to confounding factors not measured in this study.

Uveal melanoma in relation to ultraviolet light exposure and host factors.

We conducted a case-control interview study among 1277 subjects (407 patients, 870 controls selected by using random digit dial) in 11 western United States to determine whether uveal melanoma and cutaneous melanoma shared common risk factors. After adjustment for other factors, the risk of uveal melanoma was increased for those with green, gray, or hazel eyes [relative risk (RR) = 2.5, P less than 0.001] or blue eyes (RR = 2.2, P less than 0.001) when compared to brown. A tendency to sunburn after 0.5 h midday summer sun exposure increased risk for uveal melanoma (burn with tanning RR = 1.5, P = 0.02; burn with little tanning RR = 1.8, P less than 0.001; burn with no tanning RR = 1.7, P = 0.002); as did exposure to UV or black lights (RR = 3.7, P = 0.003); and welding burn, sunburn of the eye, or snow blindness (RR = 7.2, P less than 0.001). An association with uveal melanoma was also noted with an increasing number of large nevi (P = 0.04 for trend), although the individual risk estimates were not remarkable. These data suggest that host factors and exposure to UV light are risk factors for uveal melanoma.

Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer.

Forty anal paraffin-embedded tissue specimens from 24 subjects were studied for the presence of human papillomavirus (HPV) types 6, 11, 16, 18, 31, and 33, herpes simplex virus (HSV), Epstein-Barr virus, and cytomegalovirus DNA by using the polymerase chain reaction. These tissues ranged from histologically normal to invasive squamous cell carcinoma. HPV DNA was detected in the invasive anal cancer tissues of 11 of 13 subjects. HPV types were segregated by histopathological severity, with HPV 16 associated exclusively with high grade anal intraepithelial neoplasia and invasive cancer. HPV types 6 and 11 were associated with condyloma and low grade anal intraepithelial neoplasia. HPV DNA in situ hybridization studies confirmed the presence of HPV DNA in the invasive cancer tissues of 6 of 12 subjects. HPV DNA in these tissues was highly focal and primarily associated with invasive cell nests that demonstrated the greatest degree of squamous differentiation. HSV DNA was detected only in association with advanced disease, being found in the cancer tissues of 5 of 13 subjects, and in 3 of 4 subjects with high grade anal intraepithelial neoplasia, but was not detected by in situ hybridization. Epstein-Barr virus and cytomegalovirus DNA were not detected in the 40 tissue specimens. We conclude that HPV infection may play an important role in the pathogenesis of anal cancer. The association between HSV infection and high grade anal disease suggests that HSV infection may also play a role in disease progression.

Antinociceptive Effects of Botulinum Toxin Type A on Trigeminal Neuropathic Pain.

Previous studies have demonstrated that botulinum toxin type A (BoNT-A) attenuates orofacial nociception. However, there has been no evidence of the participation of the voltage-gated sodium channels (Navs) in the antinociceptive mechanisms of BoNT-A. This study investigated the cellular mechanisms underlying the antinociceptive effects of BoNT-A in a male Sprague-Dawley rat model of trigeminal neuropathic pain produced by malpositioned dental implants. The left mandibular second molar was extracted under anesthesia, followed by a miniature dental implant placement to induce injury to the inferior alveolar nerve. Mechanical allodynia was monitored after subcutaneous injection of BoNT-A at 3, 7, or 12 d after malpositioned dental implant surgery. Subcutaneous injections of 1 or 3 U/kg of BoNT-A on postoperative day 3 significantly attenuated mechanical allodynia, although 0.3 U/kg of BoNT-A did not affect the air-puff threshold. A single injection of 3 U/kg of BoNT-A produced prolonged antiallodynic effects over the entire experimental period. Treatment with BoNT-A on postoperative days 7 and 12, when pain had already been established, also produced prolonged antiallodynic effects. Double treatments with 1 U/kg of BoNT-A produced prolonged, more antiallodynic effects as compared with single treatments. Subcutaneous administration of 3 U/kg of BoNT-A significantly inhibited the upregulation of Nav isoform 1.7 (Nav1.7) expression in the trigeminal ganglion in the nerve-injured animals. These results suggest that antinociceptive effects of BoNT-A are mediated by an inhibition of upregulated Nav1.7 expression in the trigeminal ganglion. BoNT-A is therefore a potential new therapeutic agent for chronic pain control, including neuropathic pain.

Intracisternal administration of chemokines facilitated formalin-induced behavioral responses in the orofacial area of freely moving rats.

The present study investigated the effects of intracisternal administration of MCP-1, Rantes or IL-8 on pain transmission in the orofacial area. We also investigated mechanisms of hyperalgesic responses produced by intracisternal administration of IL-8. An orofacial formalin test was employed to assess the effects of chemokines on nociceptive processing. For each animal, the number of behavioral responses and the time spent grooming, rubbing and/or scratching the facial region proximal to the formalin injection site was recorded for nine successive 5-min intervals. Intracisternal administration of MCP-1, Rantes or IL-8 significantly increased formalin-induced scratching behavioral responses in the orofacial area. Intracisternal pretreatment with indomethacin, a non-selective cyclooxygenase inhibitor, did not block IL-8-induced hyperalgesia. Pretreatment with 100 microg propranolol, a non-selective beta-adrenergic receptor antagonist and 50 microg atenolol, a selective beta(1)-adrenergic receptor antagonist, inhibited the number of scratches and the duration of scratching produced by 1 ng of IL-8 injected intracisternally. These results indicate that intracisternal administration of chemokines produce a hyperalgesic response with an orofacial inflammatory pain model and that the IL-8-induced hyperalgesia is mediated by central beta(1)-adrenergic receptor.

Cutaneous melanoma in women: ovulatory life, menopause, and use of exogenous estrogens.

Factors related to menopause and use of exogenous hormones other than p.o. contraceptives were examined in 452 women ages 25-59 who were diagnosed with cutaneous malignant melanoma. Control subjects for this population-based study in the San Francisco Bay Area were 930 women of the same age. An increased risk was observed for superficial spreading melanoma (SSM) in women who reached natural menopause after age 55 [odds ratio (OR), 3.6; 95% confidence interval (CI), 1.1-11.1], and for women who had had a bilateral oophorectomy within 9 years of their diagnosis with SSM (OR, 2.2; CI, 1.1-4.5). A somewhat elevated risk of melanoma after natural menopause or hysterectomy was no longer statistically significant after adjustment for exogenous hormone use. Prolonged use of p.o. exogenous hormones after hysterectomy for women who had retained at least one ovary was associated with an increased risk of SSM (OR, 5.4; CI, 1.5-19.3), and use of these products for fewer than 5 years after bilateral oophorectomy also was associated with an elevated risk of SSM (OR, 2.9; CI, 1.0-7.8). Conjugated estrogen use was associated with somewhat elevated risks for SSM after hysterectomy with one ovary retained (OR, 2.7; CI, 0.97-7.3) and after hysterectomy with bilateral oophorectomy (OR, 2.1; CI, 0.86-5.0). There was a suggestion of a trend for increased risk of SSM with increased dosage of conjugated estrogens after hysterectomy (P for trend = 0.07). Use of vaginal creams that contained estrogen also was associated with an increased risk of SSM (OR, 1.8; CI, 1.0-3.3).

Cutaneous melanoma in women: anatomic distribution in relation to sun exposure and phenotype.

An analysis of the relationship between the anatomic site of cutaneous melanoma, sun exposure, and phenotype was conducted in 355 women with histologically confirmed superficial-spreading melanoma and in 935 control subjects. The most frequent site for superficial-spreading melanoma was the leg. However, when major sun-related and phenotype risk factors were examined by site, risk ratios were lowest for melanomas that occurred on the leg. A history of frequent sunburns during elementary or high school, increased number of self-assessed large nevi, and blond hair were more strongly associated with melanoma sites other than the leg. Tumors on the trunk were more likely than tumors at other sites to be associated with histological evidence of a preexisting nevus. Results of this work indicate that associations between melanoma phenotypic factors may differ by anatomic site.

Characteristics of women by smoking status in the San Francisco Bay Area.

To better understand why smokers are more likely to develop cervical cancer than nonsmokers, we investigated laboratory and demographic differences between the two groups. Women between the ages of 18 and 49 who attended eleven community clinics in the San Francisco Bay Area were studied to investigate differences between smokers and nonsmokers. The 332 smokers and 365 nonsmokers were queried about smoking habits, sexual and reproductive history, and recent diet. Cervical mucus specimens were cultured for yeast, lactobacillus, and other microorganisms. Results showed that white Hispanic women were less likely to smoke than white non-Hispanic women. Smokers, when compared to nonsmokers, consumed larger quantities of coffee, soft drinks, liquor, and beer in the 24 h prior to the interview. Women who smoked were more likely than those who did not smoke to have had first sexual intercourse before age 16, had a greater number of lifetime sexual partners, and were more likely than nonsmokers to have been pregnant. After controlling for number of sexual partners, smokers reported a history of chlamydia, gonorrhea, and/or pelvic inflammatory disease more often than did nonsmokers, and cervical mucus of smokers was more likely than that from nonsmokers to contain greater than 8500 microorganisms/ml.

Detection of mutagens in cervical mucus in smokers and nonsmokers.

The Salmonella mutagenicity test was used to analyze cervical mucus specimens from 364 smokers and 333 nonsmokers to determine whether the association between smoking and mutagenic cervical mucus that we reported previously among women diagnosed with dysplasia would apply to a larger group of healthy women (E. A. Holly et al., J. Natl. Cancer Inst., 76: 983-986, 1986). Women smokers and nonsmokers between the ages of 18 and 49 who attended eleven clinics and physicians' offices in the San Francisco Bay area for a routine Pap smear were examined to determine whether smokers were more likely to have mutagenic substances in their cervical mucus. About 4% of smokers and 8% of nonsmokers had positive mutagenicity test results (P = 0.02). Cervical mucus with a large number of microorganisms was more likely to have a positive mutagenicity test result than that with fewer microorganisms (test for trend, P = 0.01). Mutagenicity results varied by race and clinic location but were not associated with smoking behavior, sexual behavior, gynecological diagnosis, or diet. Further work is needed to develop methods to detect mutagens in specific body fluids.

Prenatal exposure to tobacco smoke and childhood brain tumors: results from the United States West Coast childhood brain tumor study.

Data from a large, population-based case-control study were analyzed to investigate the relationship between prenatal exposure to tobacco smoke and childhood brain tumors (CBTs). A total of 540 CBT patients, diagnosed between 1984 and 1991, were identified from population-based tumor registries in 19 West Coast counties that included Seattle, WA (13 counties), San Francisco, CA (5 counties), and Los Angeles, CA (1 county). Random digit dial was used to select 801 control subjects from the three geographical regions to obtain a case:control ratio of 1:2 in San Francisco and Seattle and 1:1 in Los Angeles. The data first were analyzed separately by geographical site and then were combined with adjustments made for gender, age at the time of diagnosis (or reference date of control subjects), birth year of the index child, and maternal race. No association was found between the risk of CBTs and maternal or paternal smoking before pregnancy and there was no association between CBTs and maternal smoking during pregnancy [odds ratio (OR) = 0.98; 95% confidence interval (CI) = 0.72-1.3]. A slightly increased OR for CBTs was found for paternal smoking during pregnancy in the absence of maternal smoking (OR = 1.2; 95% CI = 0.90-1.5) and for maternal exposure to passive smoke from any source (OR = 1.2; 95% CI = 0.95-1.6). The results of this analysis are consistent with results from several prior epidemiological studies that showed no significant association between CBTs and maternal smoking before or during pregnancy or maternal exposure to passive smoke during pregnancy.

Rapidly alternating radiotherapy and high dose cisplatin chemotherapy in stage IIIB non-small cell lung cancer: results of a phase I/II study.

Alternating radiotherapy and chemotherapy increases tumor cure rates in some animal models with reduced normal tissue damage compared to sequential use of these modalities. To test this concept in non-small cell lung cancer, 23 patients with predominantly Stage IIIB disease were treated on a Northern California Oncology Group pilot study of alternating radiotherapy and high dose cisplatin. Radiotherapy consisted of 6000 cGy delivered in three separate 10-day courses of 200 cGy/fraction/day during weeks 1 and 2, 5 and 6, and 9 and 10. High dose cisplatin, 100 mg/m2 in 3% saline, was administered on weeks 3 and 4, 7 and 8, 11 and 12, and 15 and 16. The response rate in 22 eligible patients is 73% (16/22) with four complete responses and 12 partial responses. Feasibility of this approach is demonstrated by 20/22 patients completing radiotherapy and a median of 2.5 courses of chemotherapy administered. Median survival time is 14.2 months (range 2-40+ months). One- and 2-year survival rates are 64% (14/22) and 41% (9/22), respectively. Hematologic, renal, and radiation-related toxicities were significant but manageable. We conclude that rapid alternation of radiotherapy and a high dose intensity cisplatin regimen is feasible in Stage IIIB non-small cell lung cancer, with a high response rate and acceptable toxicity. The long-term impact on local control and survival remains unclear, although preliminary survival data are encouraging in this poor prognosis population. Further studies of this concept are warranted.

Highly anaplastic astrocytoma: a review of 357 patients treated between 1977 and 1989.

Between May 1977 and August 1989, 357 patients (199 male, 158 female; median age 40 years) with highly anaplastic astrocytomas other than glioblastoma multiforme were treated according to any of several protocols used in studies by the University of California, San Francisco, and the Northern California Oncology Group. The data evaluated were age, Karnofsky Performance Score, survival, time to tumor progression, therapy, and the effect of treatment at the time of progression. The records of 219 patients were taken from the University of California database, and those of the other 138 were taken from the Northern California Oncology Group computer files. Their median Karnofsky Performance Score was 90% (range 40-100%), the overall median survival was projected as 170.9 weeks, and the median time to first tumor progression was 127.3 weeks. The median survival time measured after the first progression was 41.3 weeks. Age and Karnofsky Performance Score had a significant influence on survival and on time to the first tumor progression, whereas extent of surgery and the use of interstitial brachytherapy in the initial therapy did not. We conclude that these patients can expect a median survival of over 3 years, that young age and high Karnofsky Performance Score have a positive influence on survival, and that salvage therapies can extend survival after the onset of tumor progression for nearly a year. Although it did not lengthen survival when used in initial therapy, interstitial brachytherapy used at the time of tumor progression was associated with increased survival.

Thermoradiotherapy of recurrent malignant brain tumors.

In an attempt to improve local control and survival over those achieved with brain implant alone, a Phase I/II study of interstitial thermoradiotherapy was undertaken for recurrent malignant gliomas and recurrent solitary brain metastases. Between June 1987 and September 1990, 49 tumors in 48 patients were treated with thermoradiotherapy, including 26 glioblastoma multiforme (GM), 16 anaplastic astrocytomas (AA), 4 adenocarcinomas, and 3 melanomas. Patient age ranged from 18 to 71 years and Karnofsky Performance Status from 40 to 90. Stereotactically implanted catheters were used for both hyperthermia and brachytherapy. Hyperthermia was administered immediately before and after brachytherapy, heating as much of the tumor as possible to 42.5 degrees C for 30 min using helical coil microwave antennas. High-activity iodine-125 sources delivered tumor doses of 32.6 to 63.3 Gy. Complications included reversible neurologic changes in 13 patients, 9 seizures, 4 infections, 1 deep venous thrombosis with pulmonary embolus, and 1 scalp burn. Eighteen patients underwent reoperation for tumor and/or necrosis. Follow-up ranged from 9 to 166+ weeks. The median follow-up for living patients with GM and AA was 37 weeks and 92 weeks, respectively. Actuarial median survival was 47 weeks for patients with GM. For patients with AA, actuarial survival was 65% at 18 months and median survival has not yet been reached. Multivariate analysis showed a strong correlation between freedom from local tumor progression and "T90" temperature or minimum tumor temperature. Interstitial brain thermoradiotherapy is now being evaluated in a randomized Phase II trial for previously untreated GM.

Evaluation of bromodeoxyuridine in glioblastoma multiforme: a Northern California Cancer Center Phase II study.

In a study activated in 1983 and closed in 1987, the Brain Tumor Research Center of the University of California and the Northern California Cancer Center evaluated the effect of bromodeoxyuridine in the treatment of glioblastoma multiforme. A total of 160 patients were evaluable of 173 entered. Patients were to receive a bromodeoxyuridine infusion of 0.8 g/m2 daily over 24 hours for 4 days of each of 6 weeks of radiotherapy directed to the tumor plus a margin delivering a total of 60 Gy. Eligibility requirements included Karnofsky performance status greater than or equal to 70, biopsy or resection and central pathology review by one of the authors. Following radiotherapy patients were to receive chemotherapy with procarbazine, CCNU, and vincristine for 1 year. Median survival was 55.7 weeks and time to failure, 34.5 weeks for the evaluable group of 160 patients. In a univariate analysis the variables that influence survival and time to failure were: age, Karnofsky performance status, bromodeoxyuridine dose and the delivery of at least one procarbazine, CCNU, and vincristine cycle following radiotherapy. In multivariate analysis, age, Karnofsky performance status, and bromodeoxyuridine dose remain significant for time to failure; age and Karnofsky performance status remain significant for survival.

Assessment of prescribed increases in physical activity: application of a new method for microprocessor analysis of heart rate.

A portable solid-state recorder-display system was used to measure and analyze heart rate during the waking hours of 3 consecutive days in free-living sedentary normal middle-aged men who were randomized to undergo 3 regimens of physical activity during a 12-week period: low-intensity exercise training at home (n = 21), high-intensity exercise training at home (n = 23) and customary activity (n = 20). This was done to determine whether the system could detect changes in heart rate and, indirectly, in physical activity within the 3 groups. In both training groups the percentage of total recorded time spent within the prescribed high or low heart rate range recorded at 6 or 12 weeks increased significantly (p less than 0.05), whereas control subjects showed no increase above baseline values. Peak oxygen consumption increased by 8% and 17% in men undergoing low- and high-intensity training, whereas in control subjects it did not change. This solid-state system reliably measures prescribed increases in heart rate and provides an indirect measure of physical activity in normal sedentary men undergoing exercise training at home.

Effects of low- and high-intensity home-based exercise training on functional capacity in healthy middle-aged men.

The effects of 12 weeks of home-based exercise training on peak oxygen consumption (VO2 max) in healthy sedentary middle-aged men, mean age 49 +/- 6 years, were evaluated. Twenty-one men trained at low intensity, 23 trained at high intensity and 20 were control subjects. Individually prescribed low- and high-intensity training was performed 5 times per week within a range of 42 to 60% and 63 to 81% of baseline VO2 max, corresponding to average heart rates of 102 to 122 and 128 to 148 beats/min, respectively. Caloric expenditure per training session approximated 350 kcal in both groups; adherence was at least 90% in both groups. VO2 max increased 8% in patients who trained at low intensity, 17% in those who trained at high intensity (both p less than 0.001), and not at all in control subjects. Low-intensity exercise training at home significantly augments functional capacity in healthy sedentary middle-aged men.

Assessment by a microprocessor of adherence to home-based moderate-intensity exercise training in healthy, sedentary middle-aged men and women.

Research in exercise training of healthy persons, which has been conducted almost exclusively in supervised group programs, is relatively expensive for the investigator and inconvenient for the participant. To overcome these obstacles, self-monitored moderate-intensity home-based exercise training was prescribed for 28 middle-aged men and 26 middle-aged women. The median energy expenditure prescribed for each of 5 weekly exercise sessions was 4 cal/kg body weight, or 317 kcal for men and 265 kcal for women, corresponding to a median duration of 45 and 60 minutes, respectively. In the next 24 weeks, peak oxygen uptake increased 13.7% in men who exercised, from 31 +/- 4 to 37 +/- 4 ml/kg/min, and 10% in women who exercised, from 26 +/- 4 to 29 +/- 5 ml/kg/min (p less than 0.001 for both comparisons). The proportion of prescribed caloric expenditure per session, which was documented by a solid-state heart rate recorder, was 108% in men and 90% in women. The duration of training at heart rates above the prescribed range approximated 10 minutes per session for both men and women; the proportion of total caloric expenditure represented by exercise at heart rates exceeding the prescribed limit was 9% for men and 4% for women. The proportion of time spent within the prescribed heart rate range during training sessions was 76% for men and 84% for women. Training-induced musculoskeletal problems were reported by 6 men and no women. No subject sought medical attention and all resumed training within 1 week.(ABSTRACT TRUNCATED AT 250 WORDS)

Cost-benefit analysis of early return to work after uncomplicated acute myocardial infarction.

The economic consequences of an Occupational Work Evaluation designed to identify low risk patients recovering from uncomplicated acute myocardial infarction (AMI) and hasten their return to work was evaluated in a randomized trial. Two hundred one employed, clinically low risk men recovering from AMI were randomized to undergo an intervention (intervention group, 99 patients) consisting of an Occupational Work Evaluation or to receive usual care (usual care group, 102 patients). The time to return to work was reduced from 75 days in usual care patients to 51 days in intervention patients (p less than 0.002). Significant differences were found between groups for medical costs and occupational income during follow-up. Total medical costs per patient were lower in the intervention patients than in the usual care patients in the 6 months after AMI ($2,970 vs $3,472). Occupational income per patient was higher in intervention patients than in the usual care group in the 6 months after AMI ($9,655 vs $7,553). The per capita benefit accounting for medical costs and occupational income was $6,685 for intervention patients and $4,081 for usual care patients. Projected to the greater than 300,000 low risk, employed survivors of AMI annually in this country, the savings generated by the Occupational Work Evaluation could yield an annual economic benefit greater than 800 million dollars.

Immortalization of human embryonic fibroblasts by overexpression of c-myc and simian virus 40 large T antigen.

SV40 large T antigen, a viral oncoprotein, is known to immortalize human diploid fibroblast by soaking up cellular RB and p53, but its frequency is extremely low. Additional genetic alteration is necessary for single-step immortalization. We attempted to find out what this alteration is by overexpressing cellular signal mediator genes; c-myc and cyclin D frequently amplified in many cancer cells. Overexpression of cyclin D did not affect the immortalization, but, overexpression of c-myc along with T antigen could immortalize normal human diploid fibroblast. Several cellular markers tested during immortalization process showed that p21, a cyclin-dependent kinase inhibitor and a marker of cellular senescence, disappeared in the life span-extended cells by T antigen and in the immortalized cells by c-myc. p21 was, however, elevated in the senescent cells and in the cells of crisis. Interestingly, p16 was upregulated whenever T antigen is overexpressed. Telomerase activity was also activated only in the immortalized cells. These results suggest that overexpression of c-myc contributes to immortalization of human diploid fibroblast by activating telomerase activity and suppressing p21 activity.