Every theory and all research assumes, either explicitly or implicitly, a scientific philosophy. Making the philosophy of cancer research explicit is likely to improve our understanding both of what we know and what we still need to discover. The implications for cancer research of three different philosophies of science are therefore outlined here: 1) reduction-mechanism; 2) holism; and 3) complementarity. We show that each of these philosophies leads to a different notion of causation, a different expectation of what represents a valid explanation of cancer, and thus to different problems that are addressed by different types of experiments. We conclude that the development of an appropriate philosophy of science is not only a relevant but necessary element in research on carcinogenesis.

Humans↗

PubMedDate not supplied

History of cancer research in nosological perspective.

Contrary to conventional wisdom progress in cancer research has not followed a linear course, but rather a torturous capricious path, often guided by the prevailing concepts of disease (nosology). Various theories appear, disappear and reappear all the time. Periods with rapid progression alternate with periods of stagnation. Really new ideas emerge rarely in oncology. Most of the so-called new ideas are modifications of older concepts i.e. old wine in new skins. Moreover existing oncological theories brought under the umbrella of a new nosological paradigm may change drastically and often get a totally new meaning. As a consequence older theories may linger on over centuries but may be modified to such an extent that the original concepts are barely recognisable. Progress in oncology is characterised by periods of rapid progress alternating with periods of apparent stagnation which with hindsight were nevertheless periods in which new concepts were in statu nascendi. The history of oncology provides still a source of inspiration, since older ideas may be worth reconsidering.

History, 20th Century↗

PubMedDate not supplied

A 4-mutation model of carcinogenesis for tumour suppressor genes.

Human life can be described as the clonal development of a fertilized egg. During cell proliferation in this clone among others cancer-specific mutations arise. Supposing that about 10(16) cells are produced in a lifetime; that the mutation frequency is about 10(-6) per gene per cell generation; that cells can go through about 60 cell divisions; and that cancer arises about once in a lifetime, carcinogenesis is likely to depend on 4 cancer-specific mutations. The advantage of a 4-mutation model over a multimutational model is that it implies far more predictions that can be tested. The 4-mutation model accurately predicts the age/incidence relation of tumors and the prevalence of cancer in the various organs. It further explains the increased tumor incidence in persons with an inherited cancer gene; and the well-known histological stages of carcinogenesis.

Cell Transformation, Neoplastic↗

PubMedDate not supplied

Evaluation: complementarity and contradictoriness of cancer theories. A genetic perspective.

In this Chapter we evaluate complementarity and contradictoriness regarding theories and data of carcinogenesis described in this issue. Most theories and data are compatible with a multimutation model of carcinogenesis. There are a few authors having severe criticism regarding this mainstream. From a view of philosophy of science such criticism is valuable and this type of papers deserves careful evaluation. Zajicek has the most serious criticism. He argues that cachexia, due to the absence of essential molecules, induces the tumor which tries to produce these missing essential molecules. So, in his view, cachexia causes cancer instead of cancer cachexia. The implication is that cachexia should be treated. Duesberg argues that cancer is due to an imbalance of chromosomes rather than to cancer specific mutations. A few points and implications seem important: (a) Duesberg does not really object to a multimutation model; (b) he wants to defend the view that cancer can also be due to chromosomal imbalance, and (c) cancer due to chromosomal imbalance cannot be inherited, in contrast to cancer based on a mutation.

Cell Transformation, Neoplastic↗

PubMedDate not supplied

Perilesional IL-2 treatment of a VX2 head-and-neck cancer model can induce a systemic anti-tumour activity.

BACKGROUND: Head-and-neck cancer is associated with impaired cell-mediated immune reactivity. A rabbit model with VX2 Squamous Cell Carcinoma transplanted into both auricles was used to test the effects of a regimen for local Interleukin 2 (IL-2) therapy, optimal in murine tumour models. MATERIALS AND METHODS: Peri-tumoural IL-2 treatment started when one of the tumours exceeded 2 cm2 and consisted of 100,000 or 300,000 Chiron Units IL-2 or only solvent during 5 consecutive days. RESULTS: In 4 out of 12 (33%) rabbits the treated primary tumours regressed completely, simultaneously with the non-treated contra-lateral tumours. Also metastases in draining lymph nodes of both treated and untreated primary tumours regressed in three of these animals. Tumour cells injected in the cured animals were rejected. The histology of the regressing tumours in cured cases showed an active granulomatous reaction with a histiocytic response, splitting up of tumour islands, and fibrinoid obstruction of blood vessels. CONCLUSION: These findings showed local and systemic therapeutic effects of this local IL-2 regimen in a VX2 head-and-neck cancer model.

Animals↗

PubMedDate not supplied

A case of hepatocellular carcinoma (HCC): treatment with local application of alcohol and interleukin 2 (IL-2).

A case of an inoperable hepatocellular carcinoma due to liver cirrhosis is presented. Surgical treatment was not clinically warranted. So we decided to induce tumor necrosis by intratumoral injections of 10 mL of ethanol followed by two treatments with 9 x 10(6) U Chiron interleukin-2 with an interval of 1 month. This ethanol-interleukin-2 cycle was repeated three times with intervals of 6 months. Interleukin-2 injections were given by a fine needle, under ultrasound control in the periphery and in the center of the tumor. The initial size of the tumor was 55-60 mm. During the follow-up period of 2 years the tumor size remained relatively unchanged. The patient died due to gastric hemorrhage. The treatment elicited no adverse clinical effects. The clinical status improved greatly after this treatment. Local interleukin-2 application after alcohol-induced tumor ablation might be an alternative if surgical treatment is not warranted.

Aged↗

PubMedDate not supplied

Concepts in immunotherapy of cancer: introduction.

Explore the source record for details and available documents.

BCG Vaccine↗

PubMedDate not supplied

Effective immunotherapy with local low doses of interleukin-2.

IL-2 treatment for metastatic tumors in man is usually given systemically with high doses, often in conjunction with large numbers of LAK-cells. Complete tumor regression is obtained in less than 10%, this treatment causes severe toxicity, and culturing of LAK-cells is laborious and expensive. In this paper we demonstrate that small amounts of locally applied rIL-2 alone, if given at the right time, can cure about 70% of DBA/2 mice with large metastasized syngeneic SL2 lymphoma comprising 4-10% of the total body weight, a tumor load hitherto considered fatal. Moreover, 3 out of 5 cows with ocular squamous cell carcinoma (BOSCC) of 1 x 1 up to 3 x 4 cm were cured with low doses of rIL-2 only. Taken together, we have now tested 11 tumors in animals. No antitumor effect was observed in EL4 lymphoma in C57BL mice. Partial antitumor effects were detected in RBL5 lymphoma in C57BL mice, stomach carcinoma in BALB/c mice, MOT-carcinoma in C3H mice, liver carcinoma in guinea pigs and bovine vulval papilloma/carcinoma. Complete tumor regression was obtained in SL2 lymphoma, L5178Y lymphoma, L1210 lymphoma, and P815 mastocytoma in DBA/2 mice and in bovine ocular squamous cell carcinoma. Low doses of locally injected IL-2 induce systemic immunity, as shown in DBA/2 mice bearing syngeneic SL2 lymphoma cells. We conclude that local low dose treatment can be effective and results in a high cure rate in several tumor models. In the DBA/2-SL2 lymphoma model this treatment is 100-1000 times more effective than any form of immunotherapy we have tested during 20 years in this model.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Mechanisms of tumor regression induced by low doses of interleukin-2.

We have demonstrated that local treatment with low doses of IL-2 can cure mice bearing a large burden of metastasized SL2 lymphoma. Different mechanisms lead to rejection of ascitic SL2 tumor and solid s.c. SL2 tumor. For local rejection of ascitic tumor cytotoxic T-lymphocytes were essential, whereas the cytotoxic activity of macrophages was also important for tumor rejection. In distant solid tumors very few infiltrating lymphocytes and macrophages were present. Nevertheless, IL-2 treatment rapidly induced necrosis that seemed to be caused by stasis of blood flow in the tumors. This may be mediated by the local release of cytokines like TNF. We conclude that both cytotoxic activity and the production of cytokines by T-cells is essential for IL-2 induced systemic tumor rejection.

Animals↗

PubMedDate not supplied

Tumour regression by IL-2 mediated stagnation of blood flow.

The histology of Interleukin-2 induced tumour regression is presented. DBA/2 mice were injected simultaneously ip (intraperitoneally) and sc (subcutaneously) with 2 x 10(4) and 2 x 10(5) syngeneic SL2 lymphosarcoma cells, respectively. After treatment with 20,000 U IL-2 given ip at days 10-14, 50% of these mice survive. Histological analysis of the sc tumours showed that stagnation of blood flow and an occurrence of sudden massive necrosis were indicative of tumour regression. We hypothesize that peritoneal lymphocytes, activated by the ip tumour cells and IL-2, home in the sc tumour. There these activated lymphocytes produce lymphokines and trigger off other infiltrate cells to do similarly. This causes vascular leakage which leads to an increased intratumoural interstitial hydrostatic pressure. Subsequently circulatory obstruction and tumour necrosis occurs.

Animals↗

PubMedDate not supplied

Immunotherapy of bovine ocular squamous cell carcinoma: isolation, culture and characterization of lymphocytes present in the tumor.

Bovine ocular squamous cell carcinoma (BOSCC) is sensitive to intralesional immunotherapy with BCG or recombinant human IL-2 (rhIL-2). The mechanism of tumor regression is as yet unclear. Alterations in the concentration of IL-2 (and possibly other factors) in the tumor, due to regional injection or induction by BCG, may induce killer cell activity and thus tumor regression. To investigate this, lymphocytes were isolated by mechanical fractionation of biopsies of BOSCC. Growth, phenotypical, and functional characteristics were studied. TIL could be isolated and grown from all biopsies of BOSCC. An estimated increase in cell number of 50-150 fold was observed during 5-7 weeks of culture. FACS analysis of a limited number of the TIL cultures showed a characteristic shift in phenotypes until day 28 of culture. CD2+ cells (50-70%), and as a consequence of this CD2- cells, remained stable in number. The number of CD8+ cells increased. CD4+ cells were detected in low numbers by day 28. Prolonged culture resulted in an increase of CD2- gamma delta + cells, CD2+4-8- cells, and occasionally of both CD8+ and CD2+ cells. In 51Cr release assays TIL showed cytotoxicity for BOSCC-derived tumor cell lines in general, which increased transiently by cocultivation with tumor cells. Killing of YAC-1, and P815 was far less efficient. Preferential killing of autologous cell lines was not seen. In conclusion, TIL from bovine ocular squamous cell carcinomas can be cultured in the presence of rhIL-2, which induces cytotoxic activity for BOSCC-derived tumor cells. Cells responsible for killing in vitro and potentially for regression of the tumor after immunotherapy with BCG or rhIL2 cannot yet be identified. Depletion and blocking experiments are being conducted in order to identify the cells (CD2+8+, CD2-gamma delta + or other CD2 +/-) responsible for killing.

Animals↗

PubMedDate not supplied

The transition of benign to malignant in epithelial and mesenchymal tumours.

Following publication in this journal of a 4 mutation-model of oncogenesis some points of controversy emerged which are discussed. In particular an explanation is offered for the differences in histogenesis of epithelial and non-epithelial tumours. Some clinical features of benign tumours are also clarified.

Carcinoma↗