Tumor-Suppressor Genes and Oncogenes

OBJECTIVES Describe the differences between tumor suppressor genes and oncogenes, and give three examples of each. Describe the concepts of Knudson’s two hit hypothesis and multi-step carcinogenesis. Explain the basic biological differences, at a molecular genetic level, between cancers that occur in early childhood and those that occur in adults. Explain the difference between the pattern of inheritance of an inherited cancer at the physical level versus at the cellular level. Explain how to differentiate between sporadic and germline forms of retinoblastoma.

Dose modification consisted of giving interferon on alternating days as long as necessary to alleviate symptoms, and 25% dose reduction of DTIC in case of grade 3 or more haematological toxicity, or nausea.
Evaluation of toxicity followed the WHO guide lines (WHO Handbook, 1979). A complete response was defined as the complete disappearance of all signs of disease, a partial response as the decrease in the sum of the product of perpendicular diameters of all measurable tumour lesion of at least 50%, without progression of any lesion or development of new lesions. A response had to last a minimum of 1 month. Progressive disease was defined as an increase in the product of parameters of more than 25%, or formation of new lesions.
Twenty-six patients received a total of 111 courses. Patient characteristics are given in Table I Toxicity was mainly due to nausea and vomiting after DTIC in the first 14 patients, but this toxicity was completely abolished when ondansetron was introduced (8 mg i.v.) prior to infusion. Five patients had thrombocytopenia and/or leukopenia grade 3. Disabling fatigue requiring interferon dose adjustment occurred in five patients. No mucositis or diarrhoea occurred.
None of the patients developed signs or symptoms of brain metastases during treatment or follow-up in case of response.
Fourteen patients had progressive disease, two stabilisation of previous progressive disease for 12 + and 4 + months. Five patients had a partial remission of 2, 2, 10 +, 2 + and 4 + months. Five patients had a complete response of 2, 4, 6, 8 + and 13 + months. Median survival in all patients is 12 months.
Of the 11 female patients, six responded, with three complete remissions. The 38% response rate (95% confidence level 20-59%) is not suggestive of a major impact on response from the addition of 5-FU, in the magnitude of triplication as suggested in the first reports on synergism between interferon and 5-FU (Wadler et al., 1989). Previously, we reported a response rate of the two drugs of 35% (95% confidence 19-55%) (Mulder et al., 1990). Also, in colon cancer the combined response rate of 5-FU and interferon is levelling off to a more modest synergism (Wadler et al., 1991).
However, the absence of development of brain symptoms during treatment and in the follow-up of responders is striking in comparison to our previous experience, when 18 of 62 patients developed such symptoms (Mulder et al., 1989;Mulder et al., 1990). This finding might confirm the observation of a response of cerebral melanoma localisation following 5-FU and interferon (Jacobs et al., 1989). In the dose used here 5-FU has no important organ toxicity, although it might add to the fatigue induced by interferon. The 38% response rate also confirms the somewhat higher response rate of the combination of DTIC and interferon when compared to each drug separately (McClay & Mastrangelo, 1988;Creagan et al., 1987).
Although the majority of responses is quite short, this study confirms that occasionally complete responses can be prolonged and very worthwhile, especially if they can be reached with relatively untoxic treatment. In that respect the toxicity profile of DTIC containing regimens has changed dramatically following the introduction of ondansetron as an antiemetic. Most of our patients considered the 5-FU infusion, without ondansetron prophylaxis, as the more toxic one in comparison to DTIC.
In an interim report on this study (Mulder et al., 1991), eight responses were seen in the first 12 patients, in the next 14 patients only two partial responses were seen. In our study, this difference coincided with the introduction of ondansetron, however a causal relation is unlikely. An important predictor of response seems to be sex, and more female patients were entered during the first part of the study.