Dorris J. Hutchison

The physiologic disposition of 5‐fluorouracil and 5‐fluoro‐2′‐deoxyuridine in man

The plasma concentration and the urinary excretion of 5‐fluorouracil (FU) and 5‐fluoro‐2′deoxyuridine (FUdR), administered to patients with cancer, were determined by microbiologic assay; following regional administration, both local and systemic concentrations were measured. Rapid intravenous injections of usual clinical doses resulted in relatively high initial plasma concentrations (100 to 750 mμM per milliliter) which fell below a detectable level by 3½ hours in all patients. Generally, less than one fifth of the dose was excreted in the urine and almost all of this occurred in the first hour. The renal clearance of both drugs exceeded the glomerular filtration rate, and the clearance of FUdR was greater than FU. Gastrointestinal absorption of FU was unpredictable; FUdR was very poorly absorbed. Both drugs were degraded more completely when given by continuous infUSion, as indicated by reduced urinary excretion. After intravenous injection, the drug concentration in the cerebrospinal fluid and in neoplastic effusions was only one‐fiftieth or less that of the plasma concentration. After direct injection into neoplastic effusions, the concentration in the fluid was over 100 times that reached in the effusion after intravenous injection of the same dose. Long‐term infusion of low doses of FU into small arteries resulted in 100 or more times greater local than systemic plasma concentrations, while regional perfusion of FUdR resulted (briefly) in up to 1,000 or more times the concentration in the perfusion circuit compared to the general circulation.

CROSS RESISTANCE AND COLLATERAL SENSITIVITY STUDIES IN CANCER CHEMOTHERAPY.

Publisher Summary This chapter focuses on cross resistance and collateral sensitivity studies in cancer chemotherapy. Cross resistance means that a population resistant to a given drug is no longer susceptible to another compound while the parent population remains susceptible to both. Collateral sensitivity is defined as the greater susceptibility of a resistant population, in comparison with the parent population, to another compound. The parent population, therefore, is less susceptible than the resistant population to the action of the second chemotherapeutic agent. Cancer chemotherapy on a systematic basis is a young and rapidly progressing field. The literature on resistance to cancer chemotherapeutic agents is extremely diverse. 352 resistant mutants from 66 different biological systems have been mentioned in the chapter. Antimetabolites—namely, folic acid antagonists, amino acid antagonists, purine antagonists, and pyrimidine antagonists—have been mentioned in the chapter.

Persistence of Amethopterin in Normal Mouse Tissues.

Summary 1. Amethopterin given parenterally in various doses to normal mice resulted in the retention of a more or less constant amount of amethopterin in the liver for a period of at least 3 weeks. A decrease in the kidney concentration of amethopterin was noted. 2. CF at doses ranging from 0.5 to 30 mg/kg intraperitoneally failed to have any detectable effect 24 hours later on the concentration of amethopterin in the liver and kidneys, but caused a significant rise in the serum level of amethopterin. 3. The inhibitory substance present in the mouse liver 24 hours to 14 days after the administration of amethopterin has the same Rf value as amethopterin in 3 different solvent systems, and is therefore considered to be amethopterin.

Growth of L1210 mouse leukemia cells in vitro

Abstract Cell cultures of the L1210 (V) mouse leukemia have been isolated and maintained in vitro with parallel lines in vivo . Two of these cultures studied in some detail differed from one another in respect to morphology, growth rates and sensitivity to amethopterin, 6-mercaptopurine and 5-fluorouracil. The response of these cell-culture lines to drugs in vitro was a direct reflection of their growth rates in vitro . The two cell cultures were hypotetraploid and each possessed a subtelocentric chromosome characteristic of L1210 (V). The cell culture lines have retained their specificity for the DBA/2 mouse.

Development of Resistance to 4-Amino-N10-Methyl Pteroylglutamic Acid (Amethopterin) by Streptococcus faecalls

Summary (1) By growing Streptococcus jaecalis (ATCC No. 8043) in a medium containing successively higher concentrations of amethopterin, more than a thousand-fold increase in resistance has been achieved. (2) This amethopterin-fast variant has a slightly lower requirement for folic acid in the absence of amethopterin than the parent sensitive strain. In the absence of folic acid, however, amethopterin and certain other 4-amino derivatives of PGA can replace this folic acid requirement in the resistant strain.

Cytologic manifestations of the phagocytosis of L1210 chromosomes by L1210 cells in culture

Abstract Mouse leukemia L1210 cells in culture phagocytized from 1–20 sterile homologous L1210 chromosomes per cell. These were seen in close proximity to the nuclear membrane, both during interphase and when the cell was approaching mitosis. Chromosome-like inclusions persisted in the cytoplasm for days after phagocytosis. Pronounced cytotoxic effects and prolonged cytologic changes, such as, vacuolated cells, micronuclei, chromatin and chromosome-like inclusions were observed. It is suggested that intact homologous chromosomes from drug resistant sublines may be used in studies dealing with genetic transformations of mouse leukemia cells.

Sequential biochemical alteration to antifolate resistance in L1210 leukaemia.

ANTIFOLATE resistant, transplantable, murine tumours are most often characterized by a single change involving either the transport of drug1 or the level of dihydrofolate reductase2–5. This is understandable if one accepts the idea that multiple genetic events leading to an involvement of more than one physiological site rarely occur simultaneously. In two cases, where both physiological properties were altered6,7, the development of resistance probably occurred in a step-wise manner8. We have demonstrated this type of sequential alteration in resistance at both the physiological and cytogenetic level during repeated transplantation of a subline of L1210 leukaemia.

Distribution of Amethopterin in Normal Mouse Tissues Following Intravenous Injection.

Summary 1. The concentration of ametho-pterin in the serum, liver, kidney, spleen, lungs and muscle of normal mice at intervals following intravenous injection of 0.5 mg/kg has been ascertained. 2. The relative concentrations of amethopterin in the tissue appeared to parallel the folic acid and CF content viz. liver, kidney, and spleen in descending order. No significant quantity of amethopterin was found in the lungs or muscle. 3. Ametho-pterin-like activity was found to be still present in the liver and kidney in relatively large quantities 24 hours after injection although the serum level had reached or approximated zero in 4 hours.

Utilization of pteroylglutamic acid antagonists for growth by a strain of Streptococcus faecalis.

Summary I. S. faecalis/A, an organism made resistant to amethopterin, grew well on a series of PGA antagonists except those with a methyl group in the 9 position. 2. This culture was also more efficient than the parent strain of S. faecalis in the utilization of PGA analogs that served as growth factors for both organisms, with the notable exception of CF. The amount of CF (leucovorin) required for HMG was approximately the same for each strain. 3. Aminopterin was as effective as PGA in reversing the toxicity of aninopterin and adenopterin in the growth of 5. faecalis/A.

Development of Resistance to 4-Amino-N10-Methyl Pteroylglutamic Acid (Amethopterin) by Leuconostoc citrovorum.

Summary 1. A two thousand-fold increase in resistance to amethopterin has been induced in L. citrovorum. Since growth was slow at this high concentration of amethopterin, the culture was maintained on a medium with 400 times the concentration of amethopterin tolerated by the parent culture. 2. This amethopterin-fast variant has been maintained in the above medium for more than 5 months without any observed physiological or morphological changes.