A rat brain tumor model was prepared by stereotactically implanting 4×104 cultured 9L tumor cells in the cerebral hemisphere. The tumor bearing rats exhibited weight loss after two weeks, developed ...neurological symptoms several days later and died 19-20 days post-implant. Tumor take was 100% and the lethal tumor weighed 279 mg. The tumors had a doubling time of 39.5 hours. Cell kinetic parameters determined by PLM curve analysis 14-16 days post-implant were: TC-19.3 hrs.; TG1-8.6 hrs.; TS-7.6 hrs.; TG2-2.9 hrs.; and TM-0.2 hrs. The growth fraction was 0.55 and the cell loss factor was 0.24. The effectiveness of combined modality therapy on this model was analyzed in terms of survival, tumor size and colony forming efficiency. BCNU administered on day 16 post-implant produced an ILS of 122% while treatment on day 10 produced an ILS of only 60%, which corresponded to a 3-3.5 log cell kill and 2-2.5 log cell kill, respectively. Microsurgical removal of tumors on days 13 and 16 post-implant produced an ILS of 28% (1 log cell kill) and 56% (2 log cell kill). Surgery performed more than 3 days before or after BCNU therapy was less effective than BCNU alone on day 16. An ILS of over 200% (< 7 log kill) was achieved when BCNU was given 1 hr. before or 1 hr. and 12 hrs. after surgery performed on day 16. BCNU was not effective when administered during the surgical procedure. Cell kinetic parameters of both perturbed and unperturbed tumor cell populations can be used to design even more effective combined modality therapy.
This investigation was designed to determine whether cell death plays a role in the antiproliferative action exerted by polyamine synthesis inhibitors. To estimate the rate of tumor cell death, we ...measured the loss of 125I from mice harboring Ehrlich ascites tumor cells in which DNA was labeled with 5-125I-iodo-2'-deoxyuridine. DL-alpha-difluoromethylornithine (0.85 mumoles/g body weight/6 h), and enzyme-activated irreversible inhibitor of ornithine decarboxylase, and methylglyoxal-bis(guanylhydrazone) (45 nmoles/g body weight/6 h), an inhibitor of S-adenosylmethionine decarboxylase, were both found to increase the rate of 125I excretion. Our data suggest that these polyamine synthesis inhibitors provoke an increase in the rate of tumor cell death beyond that normally occurring during growth, methylglyoxal-bis(guanylhydrazone) being considerably more potent than DL-alpha-difluoromethylornithine. These in vivo data were corroborated by a study where the host-mediated responses did not have to be considered. Thus, Ehrlich ascites tumor cells were adapted for suspension growth in culture and treated with methylglyoxal-bis(guanylhydrazone) or DL-alpha-difluoromethylornithine. The growth kinetics and the colony forming efficiency of the drug-treated cells clearly show that polyamine synthesis inhibitors not only slow the growth rate but also cause an increase in tumor cell death.
PDF
