The response of Dunning R3327 prostatic adenocarcinoma to IL-2, histamine and radiation

Abstract

Summary A syngeneic, androgen-sensitive Dunning R3327 rat prostatic adenocarcinoma was transplanted bilaterally in the flanks of male Copenhagen Fisher rats. Approximately 3 months after implantation, when the tumours had a median volume of 150 mm3, one group of rats was treated with histamine alone (4 mg kg-1 subcutaneously on week days), another group with human recombinant interleukin 2 (IL-2) alone (425 IU kg-' continuous infusion) and a third group with both histamine and IL-2 during 6 weeks. Tumours on one flank were irradiated (6 Gy once daily for 3 days to a total dose of 18 Gy) beginning 1 week after the onset of treatment with histamine and / or IL-2. The contralateral tumour served as the intra-animal control. The tumour volumes were determined weekly. The growth curves showed that all three drug treatments were effective in delaying growth, but when used individually did not cause tumour shrinkage. Radiation was the most effective single agent, but when used alone the shrinkage did not occur until 2 weeks after irradiation. When combined with the drugs, more rapid and extensive growth delay and/or shrinkage was seen. The growth curves showed clear differences between the different treatments. The combination of the three agents was the most effective of all. The most striking difference between radiation alone and radiation plus biotherapy was the time at which a tumour response was detectable. Thus, active biotherapy alone and especially in a combination with histamine and radiotherapy warrants further investigation as a potential therapeutic approach to prostate cancer.

Interleukin-2 and histamine in combination inhibit tumour growth and angiogenesis in malignant glioma

“…This study demonstrated for the first time, as far as we know, that histamine in combination with IL-2 reduced the growth of an intracerebral malignant glioma. The results are in accordance with earlier observations that manipulation of the immune system with histamine and IL-2 inhibits growth of extracranial experimental tumours (Johansson et al, 1998). In addition to earlier suggested immunological effects Hellstrand et al, 1994a), the present results propose that interaction with tumour angiogenesis and tumour perfusion may be mechanisms involved in the action of the combination of IL-2 and histamine.…”

“…The failure of IL-2 alone to induce a detectable tumour response in our study finds support in recent published studies (Fathallah Shaykh et al, 1998) and further emphasizes the complexity of immunotherapy in malignant glioma. An IL-2 dose of the same magnitude as used in this study has previously been seen to cause significant anti-tumour effects in extracranially located rat prostatic carcinoma and thus most probably demonstrates that an effective systemic concentration of IL-2 was achieved (Henriksson et al, 1992;Johansson et al, 1998). However, even if the dose of IL-2 was relatively high, one explanation of the lack of effect of IL-2 in our orthotopic glioma model could be that the concentration of IL-2 in the intracerebral compartment was not optimal.…”

“…Interestingly, NK cell targets seem to be of special importance in cytotoxic immune response in rat glioma (Holladay et al, 1992). Moreover, it has also been demonstrated that histamine enhances the anti-tumour effects of IL-2 and irradiation in a rat prostatic carcinoma (Johansson et al, 1998).…”

Antitumorale Wirkung von Interferonen und Interleukinen in Kombination mit Strahlentherapie

“…Die experimentelle Therapie mit IL-2 und Strahlentherapie in murinen Tumormodellen war erfolgreich hinsichtlich der Behandlung von Lungenmetastasen und Primärtumoren kurz nach Inokulation, während bezüglich größerer Primärtumo-ren keine Synergie erreicht wurde [29]. In Prostatatumoren sowohl der Ratte [32] als auch der Maus [26] wurde jedoch das Ansprechen auf Strahlentherapie durch IL-2 verbessert.…”

Endogenous natural killer cells do not play a role in antitumor effects induced by interleukin-2 in a syngeneic rat colon tumor model

“…Interleukin-2 (IL-2) reproducibly induces tumor regression in various animal models [6,12,25,29]. This cytokine has also been shown to be useful as an anticancer agent in the clinic [26±28], either as a single agent or in combination with chemotherapy, adoptively transferred immune cells or other biological response modi®ers [23].…”