ET743 is a very effective agent in chemo-sensitive and marginal chemo-resistant xenografts, but inactive in chemo-resistant tumour xenografts. The activity of ET743 in the marginally cisplatin-resistant ovarian cancer HOC18 might indicate absence or incomplete cross-resistance against cisplatin. It is recommended to include melanoma, non-small-cell lung cancer, and ovarian cancer in phase II clinical trials and to use an intermittent schedule.

These results are reasonably consistent with the clinical activity of cisplatin, but overpredict the clinical efficacy of AZQ. Since pazelliptine and retelliptine are investigational compounds, the clinical phase II studies will provide a prospective test for this model. The results of the present study and the previous one indicate that the human tumor xenograft model could be suitable for predicting the activity of novel compounds to be developed for treatment of cancer patients.

Background: Titanocene dichloride (TD) is an organometallic compound with antiproliferative properties in vitro and promising antitumor activity in preclinical in vivo models. The drug interferes with DNA, blocks the S/G₂ phase of the cell cycle and shows antiangiogenic properties. The purpose of this study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of a ‘split’ dose administration schedule (days 1, 3, 5 q 3 weeks). Patients and Method: Patients with progressive advanced cancer and a creatinine clearance > 60 ml/min qualified for a treatment with TD after standard therapies (radio-, chemo-, hormone therapy) failed. A total of 10 patients (4 females, 6 males) with a median age of 58 (range 49–68) years were treated with 80 mg/m² TD at days 1, 3 and 5 (repeated at day 22). The drug was administered as light-protected infusion within 1 h. Results: Significant side effects were as follows: nausea/vomiting, appetite loss, renal toxicity (elevation of serum creatinine and proteinuria) and liver toxicity (bilirubin and alkaline phosphatase elevation), but no myelosuppression. At the starting dose (3 x 80 = 240 mg/m² TD), renal (3 patients) or liver toxicity (1 patient) of grade 3 was judged as DLT. No further dose escalation was possible. No objective tumor remission was observed. Conclusion: The tolerability of TD cannot be improved by splitting the total dose in to three treatments every other day. Compared to previous phase I data using a 3-weekly and a 1-weekly schedule, the ‘split’ dose administration allowed no further increase of the total drug dose per treatment cycle. Thus, dose intensification by alterations of the application mode does not seem to be possible.

A total of 11 newly synthesized 2-chloroethyl-nitrosoureas and 1 2-fluoroethyl-nitrosourea with short-chain substituents were tested for their cytostatic activity on the L1210 mouse leukemia in comparison to clinically used nitrosoureas. Initial experiments showed advantages of the i.v. route for tumor inoculation. Therefore, the anatomical generalisation of tumor cells after i.v. injection was studied by bio-assay. Tumor cell determinations in different organs were 10 to 100 times higher compared with i.p. implantation. Of the new compounds 10 showed marked cytostatic activity in this tumor model by producing cures, and 5 of them must be considered as superior to BCNU, the most commonly used nitrosourea.

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Autochthonous neurogenic tumors of the rat induced by transplacental application of ethylnitrosourea were used for the first time to study their suitability as tumor models for experimental chemotherapy. Of 189 transplacentally treated rats, 87% developed neurogenic tumors. After the initial clinical diagnosis of a neurogenic tumor, additional malignant tumors often occurred. The mean number of neurogenic tumors from 62 untreated control rats increased from 1.0 per rat at the time of randomization to 1.2 as revealed by autopsy and 1.5 tumors by histological examinations. Out of all neurogenic tumors, tumors of the brain were observed in 31%, tumors of cranial nerves in 36% (90% tumors of trigeminal nerve), tumors of spinal cord in 21%, and tumors of peripheral nerves in 10%. The median survival time until natural death of 62 control rats was 228 days. Rats with tumors of peripheral nerves lived shortest, followed by rats with tumors of cranial nerves, tumors of the spinal cord, and brain tumors. Brain tumors were mainly astrocytomas and oligodendrogliomas. The survival time of untreated rats from randomization to natural death was longest for those with brain tumors, followed by tumors of peripheral nerves, cranial nerves, and tumors of the spinal cord. There was great variation in survival time from a few days to more than 6 months. To study the responsiveness to chemotherapy, 62 rats received BCNU as a single intravenous dose of 9 and later 10 mg/kg. Sixty-two untreated control rats had a median survival time of 36 days (95% confidence interval 26-52 days), the treated rats 43.5 days (26-62 days). The difference was not statistically significant. BCNU produced a remission or a no change of neurologic symptoms in 60% (37 out of 62) in comparison to 39% (24 out of 62) in the control group (p less than 0.05). The advantages and disadvantages of the present models are discussed. Due to methodical problems and the marginal response to BCNU, autochthonous neurogenic tumors of the rat are not suitable as models for chemotherapeutic studies.

Eleven human colorectal xenografts from 26 tumor lines established in nude mice in our laboratory were investigated for carcinoembryonic antigen (CEA) production. Serum levels of CEA in nude mice were markedly elevated in all cases but one, median values ranging from 3.7 to 42.8 ng/ml. Carcinoembryonic-antigen levels for ten nontumor-bearing nude mice ranged from 0.00 to 0.12 ng/ml (median value 0.07). A clear linear correlation could be demonstrated between log CEA serum levels and log tumor volumes in serial measurements. In one case, CEA was normal in the cancer patient's serum and gave the lowest value (3.7 ng/ml) in nude mice bearing the xenograft. By the indirect peroxidase technique, CEA was localized mainly on the apical cell membranes of the cancerous glands and in necrotic areas; only small amounts were detectable in the cytoplasm. Transplantation of human colorectal carcinomas into nude mice offers an excellent experimental in vivo system to study the mechanism of release, metabolism, and excretion of the marker.

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