Modulation of the antitumour activity of cisplatin alone and in combination with 5-fluoro-2'-deoxyuridine by N-phosphonacetyl-L-aspartate in murine colon carcinoma no. 26.

Modulation of the therapeutic efficacy of cisplatin (CDDP) and 5-fluoro-2'-deoxyuridine (FdUrd) alone and in combination with N-phosphonacetyl-L-aspartate (PALA) was evaluated in mice bearing colon carcinoma (C-26) using a weekly intravenous (i.v.) push schedule for 3 weeks. A non-toxic dose of PALA (100 mg/kg) was administered i.v. 24 h prior to the i.v. administration of CDDP +/- FdUrd. The maximum tolerated doses (MTD) of CDDP and FdUrd when used as a single agent were 9 and 400 mg/kg, respectively. In combination, however, the MTD of CDDP and FdUrd were 2.5 and 300 mg/kg, respectively. PALA did not significantly affect the MTD. PALA improved the antitumour activity of CDDP or FdUrd when used alone; however, the highest tumour response, 66% complete tumour regression, was achieved with a PALA modulation of CDDP and FdUrd in combination.

Pharmacokinetics and antitumor activity of epirubicin encapsulated in long-circulating liposomes incorporating a polyethylene glycol-derivatized phospholipid.

The antitumor activity of epirubicin (EPI) entrapped in long circulating "Stealth" liposomes containing a polyethylene glycol-derivatized phospholipid (S-EPI) was compared to epirubicin encapsulated in a conventional liposome formulation (L-EPI) and free epirubicin (F-EPI) against mouse colon 26 tumor in vivo. Pharmacokinetics of S-EPI and F-EPI were also compared in rats. F-EPI was distributed to tissues within minutes of injection. In contrast, when administered in the S-EPI formulation, the distribution half-life of the drug was over 22 hr. S-EPI also exhibited a reduced clearance compared to F-EPI, from 111 to less than 1.0 ml/hr. S-EPI inhibited tumor growth more effectively than F-EPI or L-EPI by causing tumors to regress and increasing survival of mice. There were 9/10 (S-EPI) compared to 0/10 (F-EPI) 120-day survivors when treatment was started 3 days after tumor implant. When treatment was delayed for 10 days, tumors, which had reached approx. 0.1-0.3 cm3 in volume, regressed in 8/10 animals receiving S-EPI, whereas in all animals treated with F-EPI the tumors progressed. L-EPI was no more effective therapeutically than F-EPI in this model. The maximum tolerated dose of S-EPI was higher than that of F-EPI. The enhanced therapeutic efficacy of S-EPI is probably related to the extended circulation time of the formulation and its accumulation in tumors.

Effects of liposome-entrapped doxorubicin on liver metastases of mouse colon carcinomas 26 and 38.

The effects of doxorubicin (DOX) and DOX entrapped in standardized liposomes [mean diameter, 0.15 micron; (DOX-Lip)] on the survival of mice bearing liver metastases of mouse colon carcinoma CT38LD (C57BL/6J mice) or CT26 (BALB/c mice) were investigated. In vitro cultured CT38LD cells were more sensitive to DOX than CT26. In vivo DOX and DOX-Lip, administered iv 10 mg/kg weekly to a maximum of five injections, increased the life-spans of mice bearing CT38LD liver metastases 32% (P less than .05) and 64% (P less than .05), respectively. DOX-Lip was more effective than DOX in prolonging survival (P less than .05). Free DOX did not significantly increase the life-spans of mice bearing CT26 liver metastases (P greater than .5), whereas DOX-Lip increased the life-spans 35% (P less than .05). The results suggest that liposomal delivery of agents to the liver can enhance therapeutic activity and could be used as an arm of protocols for adjuvant therapy of liver metastases.

Some effects of the tumor promoter 12-0-tetradecanoylphorbol 13-acetate on cell interactions in vitro.

Studies were made of the effects of the potent tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), 4-O-methyl TPA (4-O-MeTPA), and 4 alpha phorbol 12,13-didecanoate (4 alpha PDD) on the aggregation of embryonic chick cells in gyratory shaker culture, a model system useful for the study of cell adhesion and cell interactions. TPA and, to a lesser extent, 4-O-MeTPA significantly reduced the neural retina aggregate size at concentrations as low as 10(-9) M and 10(-8) M, respectively. An inactive isomer, 4 alpha PDD, had no effect up to 10(-6) M. The reduction in aggregate size appeared related to promoter activity since dexamethasone, a steroid that inhibits tumor promotion by TPA, significantly reversed the inhibitory effect of TPA. None of the agents tested affected the sorting pattern in mixed neural retina and heart cultures. The results indicate that intercellular adhesion, as determined by extent of aggregation, is reduced in the presence of TPA. This inhibition is considered to be related to the tumor-promoting activity of TPA.

Failure of actinomycin D entrapped in liposomes to prolong survival in renal cell adenocarcinoma-bearing mice.

The potential prolongation of survival of actinomycin D entrapped in liposomes was examined in Balb C/Cr mice inoculated intrarenally with renal cell adenocarcinoma. There were five groups of animals: group A, a control group, received phosphate-buffered saline 0.3 cm3 i.p.; group B received free actinomycin D 300 micrograms/kg i.p.; group C received liposomes containing actinomycin D 300 micrograms/kg i.p.; group D received a mixture of free actinomycin D 300 micrograms/kg and empty liposomes i.p.; group E received empty liposomes i.p. The best median survival was of group D (free drug) - 54 days followed by group C (liposome entrapped actinomycin D) 45.2 days and group E (a mixture of free and entrapped actinomycin D) - 42 days. In vitro studies utilizing cell lines obtained from the tumor showed no statistical difference in ID50 or in cytotoxicity between the cells treated with free actinomycin D and those treated with liposomes containing drug.