Virulizin® - A review of its antineoplastic activity

Virulizin(R) (registered trademark of Lorus Therapeutics, Inc.) is a novel biological response modifier (BRM) that enhances cell-mediated immune response to tumour cells by direct macrophage activation. The agent, an aqueous solution containing a 5% (w/v) solid material mixture comprised of inorganic salts (95 - 99% of the dry weight) and organic compounds of molecular weight < 3000 Daltons (1 - 5% of the dry weight), is provided as a sterile, injectable formulation. Virtually all the organic compounds and ionic components in the mixture have been identified by chemical and spectroscopic methods. Virulizin(R) is obtained from bovine bile by a standardised process involving solvent extraction and heat hydrolysis. In vitro studies have shown that Virulizin(R) can stimulate blood monocytes, peritoneal macrophages and alveolar macrophages from patients with malignant and non-malignant diseases to mediate a level of tumour cell cytolysis that is equal to, or greater than, that elicited in the same cells by other, more conventional biological activators. Other studies have shown that the stimulation of cytotoxic function by Virulizin(R) is insensitive to the inhibitory effects of prostaglandins and, hence, is distinct from many other activators. Furthermore, the blood monocytes of patients currently receiving cytotoxic chemotherapy showed activation with Virulizin(R). In preclinical studies, Virulizin(R) showed modest inhibition of tumour growth in a human pancreatic cancer xenograft model (T/C, 0.60; p = 0.012) and increased survival time by 8% (p = 0.046) in a murine melanoma model. Toxicity studies in rats indicated that Virulizin(R) injected intramuscularly was well-tolerated by the animals. Except for a lower rate of body weight gain in the high dose group, no toxicological effect related to treatment was observed in a chronic 13-week study (three weekly im. injections of up to 1.1 ml/kg). Mutagenicity studies with Virulizin(R) were negative. Many Phase I/II and Phase II clinical trials were carried out with Virulizin(R) to evaluate the safety and efficacy of the agent to treat cancer patients. Three of those studies involved the treatment of patients with pancreatic adenocarcinoma. The majority of patients participating in these studies were those who had failed conventional treatment including surgery or chemotherapy. Disease stabilisation was observed in patients treated with Virulizin(R), and, based on a meta-analysis of the data from the three studies, the survival of the patients treated with Virulizin(R) was better than a similar patient population receiving standard chemotherapeutic agent for that disease indication. However, randomised studies may be required to confirm the effect of Virulizin(R) on disease stabilisation and survival. In the three studies on patients with malignant melanoma, at least 69% treated with Virulizin(R) showed no additional deterioration or had improved at four weeks with response being only slightly reduced after eight weeks. In the evaluation of safety, assessed overall from these clinical studies in 200 patients treated with Virulizin(R), the number and severity of adverse events were small. In conclusion, Virulizin(R) is a novel, clinically non-toxic biological response modifier that appears to have a clinical effect on disease stabilisation and survival in patients with pancreatic cancer and malignant melanoma. However, additional randomised studies may be required to confirm those effects. Future studies on Virulizin(R) will focus on the characterisation of the active components in the agent and the development of a synthetic formulation. Subsequently, the preclinical and clinical pharmacokinetics of Virulizin(R) will be determined and studies to optimise the human dose of the agent will be carried out.