survival rate was greater than 18 months for the treated patients, compared with 3.7 months for the controls. In a parallel study, 24 patients with tumors other than hepatoma were included, and SMA-NCS was administered by various arterial routes (353). The results showed a regression of the tumors in six of nine patients with metastatic liver cancer, four of four with adenocarcinoma of the lung, and one of three patients with unresectable gallbladder tumors. Since 1995, SMA-NCS/lipiodol has been accepted in Japan for use to treat primary hepatoma. Selective tumor uptake and some pharmacological characteristics of SMA-NCS, along with some other macromolecular conjugates, have been reviewed by Griesh et al. (354).
SMA-NCS can also be used to activate macrophages, natural cells, and T cells and to induce interferon-y production (80). A DIVEMA-NCS conjugate, on the contrary, exhibited cytotoxic activity (on a molar basis) in vitro against eight cell lines and bone marrow cells similar to that observed with free NCS (355). In vivo toxicity data indicated about a 1.7-fold higher LD50 value for the conjugate than for NCS. Studies also revealed a lower distribution of the conjugate than that for NCS in bone marrow and spleen cells and, to some extent, in other organs. The biological activity of DIVEMA-NCS in plasma was about 2.2 times higher than that of NCS. Because of reduced acute toxicity, DIVEMA-NCS showed a 10 times higher antitumor activity than NCS at a high dose. At lower doses, there was no difference in the antitumor activities of DIVEMA-NCS and free NCS. The relatively low antitumor activity of DIVEMA-NCS, compared with SMA-NCS, has been attributed to its rapid clearance from the circulation (355).
The DIVEMA copolymer has also been covalently linked to methotrexate (356). This polymer spontaneously released methotrexate from the polymer backbone by hydrolysis. The DIVEMA-methotrexate conjugate (molar mass 22,000) was more effective against L1210 leukemia and Lewis lung carcinoma at optimal equivalent doses than either DIVEMA or NCS alone or the combination of DIVEMA and NCS. As such, DIVEMA also shows various biological properties. It is a well-known interferon inducer and shows activity against several solid tumors and viruses. It also possesses antibacterial, antifungal, anticoagulant, and anti-inflammatory properties and is capable of stimulating macrophage activation. Biological studies have revealed that the toxicity of DIVEMA increases with an increase in its molar mass. Low molar mass pyrans stimulate phagocytosis, whereas high molar mass copolymers decrease the rate of uptake. The inhibition of polymer metabolism also increases with an increase in the molar mass (357). Based on the passage above, Can you explain the reasons behind the relatively low antitumor activity of DIVEMA-NCS, compared with SMA-NCS, and how this relates to its clearance from the circulation?
This prompt doesn't seem malicious.