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Evidence is accumulating that the cardiotoxicity of adriamycin is a function of not only total dosage but of scheduling, with those schedules associated with low peak plasma levels of the drug being associated with significant decrease in cardiac toxicity. It is believed that adriamycin enters the cell by passive diffusion, and most cells studied, both normal and neoplastic, have an active excretory mechanism that pumps adriamycin out of the cell. If it is assumed that the myocardium has such a pump then it can be shown pharmacokinetically that those schedules associated with a low peak plasma level can, under certain circumstances, selectively protect the myocardium.

A phase III study was designed comparing the effectiveness of Hexamethyl-melamine (NSC 13875) to Dibromodulcitol (NSC 104800) in lung carcinoma. 250 of the 316 patients entered on the study were stratified into groups according to stage of disease and cell type. The results showsed Hexamethylmelamine to be more effective in patients with squamous cell carcinoma and slightly superior to Dibromodulcitol in patients with anaplastic/undifferentiated cell carcinoma, whereas Dibromodulcitol proved to be more effective in patients with adenocarcinoma.

22 patients received intravenously infused L-asparaginase (Escherichia coli) on a protocol for 5 weekly doses. 13 patients received 100 U/kg, 1 patient 500 U/kg, and 8 patients 1,500 U/kg. Only 3 of the 9 patients receiving 500 U/kg or more were able to complete the 5-week protocol. 11 of the 13 patients receiving 100 U/kg were able to complete the 5-week protocol. Significant tumor responses were not seen. CNS toxicity and allergic reactions were observed at high- and low-dose levels. There was no difference as to the degree of protein changes, BUN elevation, or liver function abnormalities at the different dose levels.

It is well recognized that the degree of toxicity, type of toxicity, and therapeutic to toxic ratio of most anti-cancer agents are dependent upon schedule. It is postulated that an optimal schedule is one that creates the largest possible difference in uptake of drug between neoplastic and normal cells, especially those cells that by their death limit the amount of drug that can be given to the patient. Specific pharmacokinetic parameters can be determined that optimize the relative distribution of drug between neoplastic tissues and dose-limiting normal tissues, and thus may permit optimization of schedule.