George J. Hill

Dimethyl triazeno imidazole carboxamide and combination therapy for melanoma IV. Late results after complete response to chemotherapy (central oncology group protocols 7130, 7131, and 7131A)

The results of three Phase III studies of DTIC in 580 patients with metastatic melanoma were reviewed to evaluate the subsequent course of 26 patients who achieved a complete response (CR) to chemotherapy. The majority (17 of 26) of these patients had soft tissue metastases. Six of the 26 patients remained in CR at last report (30–259 weeks), two died of other causes while remaining free of melanoma, and 18 relapsed and died. Ninety‐five percent of the 26 patients were alive at 1 year, and survival was 31.1% at 72 months. Seven of the eight patients with sustained remission received chemotherapy for at least 6 months after CR developed, whereas 10 of 18 relapsing patients were treated for less than 6 months after CR was achieved. Long‐term sustained CR to chemotherapy occurs in 1% to 2% of patients treated with DTIC, and late relapse is rare in patients who remain in CR for 2 years. Cancer 53:1299‐1305, 1984.

DTIC and combination therapy for melanoma: III. DTIC (NSC 45388) Surgical Adjuvant Study COG PROTOCOL 7040.

A prospectively randomized study of postoperative chemotherapy with dimethyl triazeno imidazole carboxamide (DTIC) was conducted by the Central Oncology Group from 1972 until 1976. Of 174 patients operated upon for melanoma and entered into the study, 87 were randomly selected to receive DTIC, four courses in 12 months, at 4.5 mg/kg/d × 10. One‐hundred‐sixty‐five (95%) of the cases were evaluable, including 40 high risk Stage I, 96 Stage II, and 29 Stage III cases. At a median follow‐up period of 2.5 years, the control group had a better median disease‐free interval (40 weeks vs. 73 weeks), median survival time (103 weeks vs. 133 weeks), and percentage of patients living free of disease (28% vs. 44%) than the DTIC‐treated group. While disease‐free interval appeared to be improved in the 25% of patients on DTIC therapy who developed thrombocytopenia, the overall effect of postoperative DTIC therapy was apparently not beneficial (P < 0.05).

Cancer prevention education in United States medical schools

The Cancer Education Survey collected data from 126 of 128 US Medical Schools on the current status of cancer-related educational activities for undergraduate medical students. The study was conducted by a Supervisory Committee of the American Association for Cancer Education, with funding from the American Cancer Society. The survey obtained data concerning institutional characteristics in support of undergraduate medical student cancer education, ie, administrative structures, current cancer-related curricula, sources of financial support, and anticipated changes in these characteristics. Institutions were also queried on specific topics of cancer prevention, detection, and diagnosis that might be taught as identifiable areas of instruction for medical students. Three-fourths of the institutions had a lecture on the principles of cancer screening, and, among those, nearly three-fourths classified it as a part of a required course or rotation. Detection of common cancers is taught in virtually all institutions. The least likely cancer prevention lecture topics are related to prevention and cessation of smoking, a well-verified cancer risk. Also, no consistent pattern emerges that might indicate that association with a cancer center imparts to a medical school a greater emphasis on delivery of cancer prevention topics.

Comparative Action Spectrum for Ultraviolet Light Killing of Mouse Melanocytes from Different Genetic Coat Color Backgrounds

The photobiology of mouse melanocyte lines with different pigment genotypes was studied by measuring colony‐forming ability after irradiation. The cell lines were wild‐type black (melan‐a) and the mutants brown (melan‐b) and albino (melan‐c). Four lamps emitting various UV wavelengths were used. These were germicidal (UVC, 200–280 Dm), 82.3% output at 254 nm, TL01 (UVB, 280–320 nm), 64.2% at 310–311 nm, FS20, broadband with peak output at 312 nm and Alisun‐S (UVA, 320–400 nm), broadband with peak output at 350–354 nm. Appropriate filtration reduced the contaminating UVC to nonlethal levels for the longer waverange lamps. Wild‐type melan‐a was resistant to UVC and UVA compared to the other two cell lines, but the differences were small. The melan‐c cell line was more resistant to UVB and markedly more resistant to FS20 than the pigmented lines. With the exception of FS20 responses, melan‐b was more sensitive than melan‐a to killing by the various UV lamps. There were more pyrimidine dimers (cyclobutane dimers and 6–4 photoproducts) produced in melan‐a than in melan‐c cells by UVC, UVB and FS20 lamps. Unlike melan‐c, melan‐a and melan‐b showed a strong free radical signal of melanin character with a detectable contribution of pheomelanin‐like centers. The contribution of pheome‐lanin was higher in melan‐b than in melan‐a, while the total melanin content in these two cell lines was comparable. The abundant melanin granules of wild‐type melan‐a melanocytes were well melanized and ellipsoidal, whereas those of melan‐b melanocytes tended to be spherical. In the albino line (melan‐c) the melanocytes contained only early‐stage melanosomes, all of which were devoid of melanin. The results indicate that pigment does not protect against direct effect DNA damage in the form of pyrimidine dimers nor does it necessarily protect against cell death. High pigment content is not very protective against killing by UVC and UVA, and it may photosensitize in UVB the very wavelength range that is of greatest concern with respect to the rising incidence in skin cancer, especially melanoma. It is clear from these studies that, in pigment cells, monochromatic results cannot predict polychromatic responses and that cell death from solar irradiations is a complex phenomenon that depends on more than DNA damage.

Melanin Both Causes and Prevents Oxidative Base Damage in DNA: Quantification by Anti-Thymine Glycol Antibody

The present study employs immunological methods to measure modified bases in DNA. A polyclonal antibody specific for thymine glycol was used to quantify the level of thymine glycol in calf thymus DNA gamma-irradiated in solutions containing varying concentrations of DOPA-eumelanin. Melanin decreased the number of thymine glycols produced by 200 Gy at low melanin concentrations. At high melanin concentrations, the number of thymine glycols increased. Thymine glycol was also produced in unirradiated DNA-eumelanin mixtures. DOPA-eumelanin was found to produce single-strand breaks in supercoiled phi X174 RF DNA. The breaks were measured by conversion of form I to form II as detected by agarose gel electrophoresis. The level of damage produced by melanin could be modulated by agents known either to stabilize or to scavenge active oxygen species. These studies demonstrate that melanin can both scavenge and generate active free radicals.

Preoperative intra-arterial infusion chemotherapy for advanced squamous cell carcinoma of the mouth and oropharynx

Twelve patients with advanced locoregional (Stage III and IV) squamous cell carcinoma of the oral cavity and oropharynx underwent treatment with cisplatin, vinblastine, bleomycin, and 5‐fluorouracil, given by intra‐arterial infusion, as primary adjuvant therapy, in preparation for radiation therapy and surgery. Responses were observed during or immediately after infusion therapy in 8 of 12 (67%) of patients (1 complete response, 7 partial responses). Infusion chemotherapy was followed by radiation therapy alone in five patients and by radiation and surgery in six patients. The protocol was initiated in August 1981, and six patients are now free of their primary cancer, at 21 to 36 months, whereas six have died with disease. Arterial infusion of a combination of effective antineoplastic agents is a promising method for the preparation of selected patients for radiation therapy and surgery, as it is less likely to produce serious systemic toxicity and it requires a shorter period than systemic neoadjuvant chemotherapy.

Cancer of the tonsil: Improved survival with combination therapy†

One hundred seventy‐four cases of squamous cell cancer of the tonsil (SCCT) were reviewed. Radiation therapy (RT) alone was used in 81 patients, surgery alone (S) in 19 patients, preoperative RT + S in 49 patients, and chemotherapy ([C] methotrexate plus bleomycin plus cisplatin) in 25 patients. The 5‐year survival was 83% in Stage I (n = 21), 72% in Stage II (n = 19), 23% in Stage III (n = 34), and 15% in Stage IV (n = 100). RT and S were equally effective in Stages I and II. In Stage III, the 5‐year survival for RT + S was 31% versus 11% for RT alone; and in Stage IV, the respective 3‐ and 5‐year survivals for RT + S were 24% and 15% versus 6% and 0%, respectively, for RT alone. There was an 84% response rate to C, and the patients who completed C + RT + S had 3‐ and 5‐year survival rates of 41.7% and 32%, respectively. Our results indicate that RT + S appears to offer better survival in Stage III and IV SCCT. The high response rate in early survival data seen with C + RT + S suggests a promising role for this approach.

Growth and pigmentation in genetically related Cloudman S91 melanoma cell lines treated with 3-isobutyl-1-methyl-xanthine and beta-melanocyte-stimulating hormone.

Abstract 4 clonal sublines of Cloudman S91 melanoma cells, S91/mel, S91/13, S91/6 and S91/amel, were evaluated for changes in growth, pigment content and plating efficiency during and after treatment with a cyclic‐AMP phosphodiesterase inhibitor‐melanin‐stimulating agent, 3‐isobutyl‐l‐methyl‐xanthine (IBMX) plus β‐melanocyte stimulating hormone (β‐MSH) or IBMX alone. After combined treatment, increases in melanin content on day 3 were 48, 27, 11, and 2 pg/cell in the four cell lines respectively. In each case IBMX alone was less effective than IBMX plus β‐MSH. Doubling time increased and plating efficiency decreased with increased melanization. The increases in doubling time and decreases in plating efficiency were cell line dependent. The greatest rate of increase in doubling time and decrease in plating efficiency as a function of melanin content were seen in S91/amel, which produced the least pigment. The lowest rates of increase/decrease were seen in S91/mel, which produced the most pigment. Melanin pigment induced in the cells was classified as etimelanin by EPR determination. The differential response to induction of pigmentation makes these cell lines suitable models for comparative studies on the role of melanin in pigment cell biology.

Continuous growth of human tumor cell lines in serum-free media

SummaryFive human tumor cell lines were studied for growth factor requirements and for replication in serum-free media. Of the five tumor lines HT-29 (colon carcinoma), TWI (melanoma), A-549 (lung carcinoma), Panc-1, (carcinoma of the pancreas) and EJ, (bladder carcinoma) only HT-29 and TWI grew in the serum-free medium (SFM). In a series of additional experiments, a combination of transferrin (5 μg/ml), insulin (5 μg/ml), triiodothyronine (2×10−10M), epidermal growth factor (20 ng/ml), and selenium (5 ng/ml) was added to Chee’s essential medium (CEM) without serum (C-TITES medium). The C-TITES modification of CEM was found to allow optimal replication of HT-29 and TWI cells. Both HT-29 and TWI cells have replicated continuously in C-TITES medium for periods of more than 15 mo. These cells replicate with slightly lower doubling times than in CEM supplemented with 10% fetal bovine serum. Deletion of insulin or transferrin from the C-TITES medium resulted in cessation of cell growth of HT-29 and TWI. HT-29 assumed a somewhat rounded morphology, whereas TWI grew with the characteristic fibroblastic morphology in C-TITES medium. Cell line EJ did not grow in C-TITES medium. The other two cell lines, A-549 and Panc-1, grew in C-TITES medium but their growth rate was much slower than that in SSM. Availability of cell lines that can be propagated in serum-free, hormone-supplemented medium may aid in the study of the mechanisms by which hormones influence cell growth.

Instructional methods and the use of teaching resources in cancer education curricula

The findings on cancer teaching methodology presented in this abstract come from an American Association for Cancer Education (AACE)/American Cancer Society-sponsored survey of American allopathic medical schools in 1989 and 1990 to determine how and how well cancer is presented in the medical school curriculum. Responses were received from 126 institutional and approximately 1,000 faculty respondents. Approximately one-third (368) of faculty respondents indicated the use of specific learning objectives; utilization does vary across disciplines. The lecture remains the dominant form of instructional method. Computers were reported as an instructional modality by only 16% of the faculty respondents. Prepared audiovisual instructional materials appeared to be widely utilized. Use varied from 86% for 35mm slides to 11% for video discs. Faculty favored the development of new teaching materials for ten topic areas ranging from approximately 40% for early detection and prevention to a low of approximately 25% for rehabilitation and continuing care. The survey identified an underutilization of existing outpatient facilities and tumor registries for cancer teaching purposes. The findings give rise to questions concerning the appropriateness of the match between specific instructional goals and the teaching methods employed. Eight recommendations designed to strengthen cancer training are made.