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Augmentation for intratumoral accumulation and anti‐tumor activity of liposome‐encapsulated adriamycin by tumor necrosis factor‐α in mice

The effect of recombinant human tumor necrosis factor‐α (rhTNF‐α) on anti‐tumor activity of adriamycin entrapped in small unilamellar liposomes (ADM‐Lip) has been studied using BALB/c mice bearing subdermal Meth‐A fibrosarcoma. Accumulation of i. v. injected ADM‐Lip, but not of free ADM, into tumor tissue was augmented by a single i. v. injection of rhTNF‐α. The maximum effect of rhTNF‐α was expressed when it was injected 1 hr before ADM‐Lip. This rhTNF‐α treatment did not result in increased accumulation of ADM‐Lip in normal organs. Based on these results, we treated mice bearing Meth‐A tumor with rhTNF‐α and then with ADM‐Lip 1 hr later. By 2‐cycle treatments using this regimen, tumor growth was markedly inhibited, and 5 out of 13 mice tested were cured of tumor, while treatment with rhTNF‐α alone, ADM alone, ADM‐Lip alone or rhTNF‐α plus ADM resulted neither in prolongation of survival time nor in cure of mice. Our results indicate that ADM‐Lip can express a potent and systemic anti‐tumor activity after pretreatment of animals with TNF, but only when administration of these drugs is appropriately timed.