Journal of Oncology Pharmacy Practice

Objective. Current modalities used in the treatment of cancer often cause unacceptable damage to normal tissue. Toxins targeted toward tumor cells by antibodies or growth factors have the potential to selectively kill tumor cells while leaving normal tissue intact. The purpose of this review is to provide background information on targeted toxins and current clinical studies for this new class of anti-cancer compounds.

Data sources. A MEDLINE search was conducted using the term “immunotoxins.” Relevant articles were also obtained by the systematic examination of article references.

Data synthesis. The toxins Pseudomonas exotoxin, diphtheria toxin, and ricin toxin are often used as targeted toxins. Deletion or mutation of the binding domains of these toxins decreased binding of the toxins to normal tissues. Antibodies or growth factors can be used as targeting moiety, and the resulting agents are called immunotoxins or fusion proteins, respectively. DNA technology and chemical modifications of the toxin as well as the antibody moiety led to smaller and less immunogenic targeted toxins. Smaller targeted toxins are less toxic and penetrate further into the tumor. The summary of several targeted toxins elicited during clinical trials in this review makes it clear that several targeted toxins are potential agents for the treatment of various cancers, although some problems still need to be overcome. These problems include toxicity, immunogenicity, cross-reactivity of the targeted toxin with life-sustaining tissue, heterogenicity of tumor cells, and limited tumor penetration.

Cancer joins the category of diseases involving abnormalities in the rate of proliferation of cells and is associated with uncontrolled cell division, where cells either generate their own growth-promoting stimuli or neighboring cells or do not respond to growth inhibitory signals. Protein kinase C (PKC) is one of the key elements in the tumor growth signal transduction pathways and is found to be overexpressed in several malignant cell types. A way to control cell proliferation and cell differentiation is by influencing signal transduction pathways by modulation of PKC. PKC encloses 12 different isoenzymes, and each isoenzyme is found to have a different functional property. Because specific PKC isoenzyme types are present in different (malignant) cell species, they may be an attractive target in the development of anti-cancer agents. Classification and identification of the available PKC isoenzymes in different tumor cells could be useful in targeting specific tumors. PKC also tends to be overexpressed in association with the multidrug resistance pheno-type. This concise review deals with the role of PKC isoenzymes in (tumor) cell biology and evaluates the antineoplastic agents interacting on PKC isoenzymes.

Objective. To determine whether thalidomide is an effective prophylactic agent against acute graft-versus-host disease (GVHD) and whether it exerts an effect on graft-versus-leukemia (GVL) reactivity, the drug was administered to leukemic mice that were exposed to allogeneic bone marrow transplantation.

Methods. Mice (BALB/c 3 C57BL/6) F₁ were inoculated with 10⁷ B cell leukemia cells (BCL1) and conditioned with total body irradiation followed by reconstitution with bone marrow plus splenic cells harvested from C57BL/6 mice. After transplant, mice were treated with oral thalidomide (20 mg/kg/day) for a period of 10 days.

Results. Stable chimerism was documented in all recipients with $73% (mean) donor-type C57 cells. In this semi-allogeneic murine model, thalidomide failed to prevent or alleviate the acute GVHD symptoms; however, the drug did not impair GVL reactivity. The antileukemia allogeneic effect was similar in the thalidomide and non-thalidomide-treated animals. Comparison of the GVL reactivity occurring in the allogeneically transplanted groups with that in the syngeneic recipients revealed a significant difference (P 5 0.001).

Conclusions. Although thalidomide did not exert any effect against acute GVHD, the fact that the GVL reactivity was spared holds promise for its use as a treatment modality in chronic GVHD.

Objective. To assess the contribution pharmacists make to patient care by determining the clinical outcomes associated with pharmacist interventions.

Methods. A 2-month prospective intervention study was conducted at Peter MacCallum Cancer Institute, a tertiary referral center. During the study, clinical pharmacists documented intervention episodes, patient demographical details, and the drug(s) involved. Clinical outcomes resulting from pharmacist-initiated changes to drug therapy and patient management were assessed by an independent pharmacist according to defined criteria. Outcomes were determined through review of patient medical progress notes and discussion with members of the health care team.

Results. A total of 674 interventions were documented during the data collection period. Outcomes could be assessed for 10% of the interventions reported, and 90% of these interventions resulted in documented clinical benefit. The drug classes most frequently associated with pharmacist interventions were antiemetics, antimicrobials, and analgesics.

Conclusion. This prospective study demonstrated a high rate of beneficial outcomes achieved by pharmacist interventions.

Background. In North America, epithelial ovarian cancer (EOC) is the fifth most common cause of cancer death among women. Many drugs are used in the treatment of EOC, with gemcitabine showing recent promise. The objective of this study was to determine whether gemcitabine is a beneficial treatment option for patients with EOC.

Methods. The charts of 20 heavily pretreated women (median: four previous treatment protocols, range: 1-6) with a histological diagnosis of EOC were retrospectively reviewed to determine response. Eligible patients were treated with gemcitabine at a starting dose of 800 mg/m² as an intravenous infusion on days 1, 8, and 15 of each 28-day cycle. The patients had a median age of 56 years (range 37-81).

Results. Response to treatment was assessed both clinically and serologically (CA-125 tumor marker was monitored). Of the 20 enrollees, 17 were evaluable clinically and 16 were evaluable serologically (2 were not evaluable by either technique).

There were two (12%) patients with a clinical partial response, six (35%) patients with clinical stable disease, nine (53%) patients with clinical progressive disease, and three patients that were not evaluable clinically. There were four (25%) patients with sero-logical partial response, six (38%) patients with stable serological disease, six (38%) patients with serological progressive disease, and four patients that were not evaluable serologically. Physician-reported toxicity included fatigue; however, this information was recorded inconsistently.

Conclusion. Gemcitabine showed modest activity in heavily pretreated EOC with a 12% clinical partial response rate and a 25% serological partial response rate. No serious toxicities were encountered.

Objective. In the United Kingdom, granisetron is licensed at an adult dose of 3 mg for prophylaxis of emesis due to cytotoxic chemotherapy. In the United States, however, the licensed dose is 10 mg/kg, which, for most adults, equates to 1 mg. In view of the cost implications of this difference in dosage recommendations, the local drug and therapeutics advisory committee supported a proposal to evaluate the use of the 1-mg dose for our own patients. We report the results of this evaluation in patients receiving the highly emetic drugs cisplatin and melphalan, given alone or in combination with other cytotoxics.

Design. Prospective, open, non-randomised study of patients receiving 3 mg and 1 mg of granisetron as part of their antiemetic regimen. Data collection was carried out before and after a change in hospital antiemetic policy.

Setting. A specialist oncology hospital in England.

Patients. A total of 57 patients received 3 mg of granisetron, and 70 patients received 1 mg of granisetron.

Results. There was a small increase in the incidence of nausea and vomiting following the change in the granisetron dose from 3 mg to 1 mg, but this increase was not big enough to be significant.

Conclusion. Guidelines recommending the use of granisetron at a dose of 1 mg were successfully implemented at the Royal Marsden Hospital with the potential to save the Trust over £50,000 per year without detriment to patient care.