This analysis was carried out to assess quantitative and qualitative relationships between animal and human toxicology data with anticancer drugs. Among 21 chemotherapeutic agents, one-sixth LD10 in the mouse or one-third toxic dose low (TDL) in the dog corresponded to acceptable doses in man when experimental and clinical data were obtained at identical schedules and compared on a mg/m2 basis. The mouse and the dog largely differed in their tolerance to individual drugs. One-tenth LD10 in the mouse seemed always tolerated in the dog. On the average, these species were equally relevant for establishing the initial dose in man. A similar number of dose escalation steps would have been required in phase I clinical trials if the starting dose had been based on one-tenth LD10 in the mouse or the lowest value of one-sixth LD10 in the mouse and one-third TDL in the dog. These observations indicate that the starting dose in phase I clinical trials could be safely and efficiently based on one-tenth LD10 in the mouse. Prior verification that the resulting dose is not lethal or life-threatening in the dog could add further safety to this procedure. The predictive value (PV+) in man of organ system toxicity in animals depends upon the prevalence of this toxicity in man. In our study, PV+ was high (greater than 0.85) for common toxic effects in man, i.e., gastrointestinal intolerance and myelosuppression. PV+ declined dramatically (0.05 to 0.54) with rarer toxic manifestations. There was no clear superiority of animal findings over the mere knowledge of the prevalence of these findings in man. Thus, it would appear that routine and undiscerned investigation of organ system toxicity in animals is of questionable usefulness for the clinician experienced in early clinical trials with chemotherapeutic agents.

Animals↗

PubMed1981

Cisplatin: impact of a new anticancer agent on current therapeutic strategies.

This brief overview illustrates the role of cisplatin in current cancer chemotherapy. This new agent is increasingly utilized in first line regimens for a variety of tumor types notably testicular, head and neck and bladder cancer. Large scale investigations are taking place to evaluate these regimens in combined modality approaches to early stages of these diseases.

Antineoplastic Agents↗

PubMed1980

[Chemotherapy of non-seminoma tumours of the testis (author's transl)].

During the past few years considerable progress has been achieved in the treatment of non-seminoma tumours of the testis, particularly since cisplatin was introduced. The use of this new drug in combination with other chemotherapeutic agents has resulted in complete remission in over 50% of all advanced cases, and many such remissions that have now persisted for more than two years will probably prove permanent. Thorough analysis of the various prognostic factors involved shows that the probability of response to new chemotherapeutic regimens mainly depends upon the extent of the disease and upon previous treatments. A prospective study of the value of platinum-containing drugs in the treatment of circumscribed tumours is currently under way.

Adult↗

PubMed1980

Methodology phase II clinical trial in cancer.

Explore the source record for details and available documents.

Antineoplastic Agents↗

PubMed1980

N-(Phosphonacetyl)-L-aspartate (PALA): current status.

N-(Phosphonoacetyl)-L-aspartate (PALA) is a synthetic antimetabolite exhibiting striking oncolytic properties against a wide variety of experimental solid tumors. The clinical dose-limiting factor is mucocutaneous toxicity which is reversible and dose-related. Delineation of the single-agent activity of PALA in human cancer must still await results of recently activated trials.

Animals↗

PubMed1980

Clinical implications of cisplatin pharmacology.

Extensive investigation is taking place to overcome the nephrotoxic manifestations and the gastrointestinal intolerance of cisplatin. Various modes of administration are being explored for this purpose with different schedules, infusion durations, hydration programs, and diuretic regimens. Pharmacokinetic studies suggest that such manipulations may lead to considerable variations in cisplatin excretion and in peak plasma levels of the non-protein-bound species. The clinical impact of these pharmacokinetic alterations is not currently apparent. This should be clarified with additional studies of the behavior of non-protein-bound platinum and its relationship to clinical efficacy and toxicity.

Animals↗

PubMed1980

Cisplatinumdiamminodichloride (CPDD) in chemotherapy of cancers: a phase II therapeutic trial.

We have conducted a phase II trial of cisplatinumdiamminodichloride (CPDD) which not only demonstrated its remarkable activity in embryonic carcinoma of the testes, but also in ovarian carcinoma, in melanoma, and in epidermoid carcinoma, especially of the head and of the uterus cervix. Its toxicity, manifested mainly in the digestive and renal tracts, confines its administration to hospitalized patients only. This compound is now indicated in combination therapy for the above-mentioned tumors.

Adolescent↗

PubMed1980

m-AMSA: a new anticancer agent.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA; NSC-249992) is a new anticancer agent that has undergone extensive experimental investigation. Clinical trials have recently been initiated and current data suggest a wide spectrum of antitumor activity in human cancer.

Aminoacridines↗

PubMed1980